5- substituted tetralones as inhibitors of ras farnesyl trransferase

ABSTRACT

The present invention provides novel 5-substituted tetralones of Formulas (I), (II), (III) and (IV) and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, which are useful for treating and preventing uncontrolled or abnormal proliferation of tissues, such as cancer, atherosclerosis, restenosis, and psoriasis. Specifically, the present invention relates to compounds that inhibit the farnesyl transferase enzyme.

FIELD OF THE INVENTION

[0001] The present invention relates to compounds that can be used totreat, prophylactically or otherwise, uncontrolled or abnormalproliferation of tissues. Specifically, the present invention relates tocompounds that inhibit the farnesyl transferase enzyme, which has beendetermined to activate ras proteins that in turn activate cellulardivision and are implicated in cancer, restenosis, and atherosclerosis.

SUMMARY OF THE RELATED ART

[0002] Ras protein (or p21) has been examined extensively because mutantforms are found in 20% of most types of human cancer and greater than50% of colon and pancreatic carcinomas (Gibbs J. B., Cell, 1991, 65:1,Cartwright T. et al., Chimica. Oggi., 1992;10:26). These mutant rasproteins are deficient in the capability for feedback regulation that ispresent in native ras, and this deficiency is associated with theironcogenic action since the ability to stimulate normal cell divisioncannot be controlled by the normal endogenous regulatory cofactors. Therecent discovery that the transforming activity of mutant ras iscritically dependent on post-translational modifications (Gibbs J. etal., Microbiol. Rev., 1989;53:171) has unveiled an important aspect ofras function and identified novel prospects for cancer therapy.

[0003] In addition to cancer, there are other conditions of uncontrolledcellular proliferation that may be related to excessive expressionand/or function of native ras proteins. Post-surgical vascularrestenosis and atherosclerosis are such conditions. The use of varioussurgical revascularization techniques such as saphenous vein bypassgrafting, endarterectomy, and transluminal coronary angioplasty areoften accompanied by complications due to uncontrolled growth ofneointimal tissue, known as restenosis. The biochemical causes ofrestenosis are poorly understood and numerous growth factors andprotooncogenes have been implicated (Naftilan A. J. et al.,Hypertension, 1989;13:706 and J. Clin. Invest., 1989; 83:1419; GibbonsG. H. et al., Hypertension, 1989;14:358; Satoh T. et al., Molec. Cell.Biol., 1993;13:3706). The fact that ras proteins are known to beinvolved in cell division processes makes them a candidate forintervention in many situations where cells are dividing uncontrollably.In direct analogy to the inhibition of mutant ras related cancer,blockade of ras dependent processes has the potential to reduce oreliminate the inappropriate tissue proliferation associated withrestenosis or atherosclerosis, particularly in those instances wherenormal ras expression and/or unction is exaggerated by growthstimulatory factors. See, for example, Kohl et al., Nature Med.,1995;1(8):792-797.

[0004] Ras functioning is dependent upon the modification of theproteins in order to associate with the inner face of plasma membranes.Unlike other membrane-associated proteins, ras proteins lackconventional transmembrane or hydrophobic sequences and are initiallysynthesized in a cytosol soluble form. Ras protein membrane associationis triggered by a series of post-translational processing steps that aresignaled by a carboxyl terminal amino acid consensus sequence that isrecognized by protein farnesyl transferase (PFT). This consensussequence consists of a cysteine residue located four amino acids fromthe carboxyl terminus, followed by two lipophilic amino acids, and theC-terminal residue. The sulfhydryl group of the cysteine residue isalkylated by farnesyl pyrophosphate in a reaction that is catalyzed byprotein farnesyl transferase. Following prenylation, the C-terminalthree amino acids are cleaved by an endoprotease and the newly exposedalpha-carboxyl group of the prenylated cysteine is methylated by amethyl transferase.

[0005] The enzymatic processing of ras proteins that begins withfarnesylation enables the protein to associate with the cell membrane.Mutational analysis of oncogenic ras proteins indicate that thesepost-translational modifications are essential for transformingactivity. Replacement of the consensus sequence cysteine residue withother amino acids gives a ras protein that is no longer farnesylated,fails to migrate to the cell membrane, and lacks the ability tostimulate cell proliferation (Hancock J. F. et al., Cell, 1989;57:1617;Schafer W. R. et al., Science, 1989;245:379; Casey P. J., Proc. Natl.Acad. Sci. USA, 1989;86:8323).

[0006] Recently, protein farnesyl transferases (PFTs), also referred toas farnesyl protein transferases (FPTs), have been identified and aspecific PFT from rat brain is purified to homogeneity (Reiss Y. et al.,Bioch. Soc. Trans., 1992;20:487-88). The enzyme is characterized as aheterodimer composed of one alpha-subunit (49 kDa) and one beta-subunit(46 kDa), both of which are required for catalytic activity. Highexpression levels of mammalian PFT in a baculovirus system andpurification of the recombinant enzyme in active form has also beenaccomplished (Chen W.-J. et al., J. Biol. Chem., 1993;268:9675).

[0007] In light of the foregoing, the discovery that the function ofoncogenic ras proteins is critically dependent on theirpost-translational processing provides a means of cancer chemotherapythrough inhibition of the processing enzymes. The identification andisolation of a protein farnesyl transferase that catalyzes the additionof a farnesyl group to ras proteins provides a promising target for suchintervention. Ras farnesyl transferase inhibitors have been shown tohave anticancer activity in several recent articles.

[0008] Ras inhibitor agents act by inhibiting farnesyl transferase, theenzyme responsible for the post-translational modification of the rasprotein which helps to anchor the protein product of the ras gene to thecell membrane. The role of the ras mutation in transducing growthsignals within cancer cells relies on the protein being in the cellmembrane. Inhibition of farnesyl transferase will result in the rasprotein remaining in the cytosol and, consequently, being unable totransmit growth signals. These facts are well-known in the literature.

[0009] A peptidomimetic inhibitor of farnesyl transferase B956 and itsmethyl ester B 1086 at 100 mg/kg have been shown to inhibit tumor growthby EJ-1 human bladder carcinoma, HT1080 human fibrosarcoma, and humancolon carcinoma xenografts in nude mice (Nagasu T. et al., Cancer Res.,1995;55:5310-5314). Furthermore, inhibition of tumor growth by B956 hasbeen shown to correlate with inhibition of ras post-translationalprocessing in the tumor. Other ras farnesyl transferase inhibitors havebeen shown to specifically prevent ras processing and membranelocalization and are effective in reversing the transformed phenotype ofmutant ras containing cells (Sepp-Lorenzino L. et al., Cancer Res.,1995;55:5302-5309).

[0010] In another report (Sun J. et al., Cancer Res., 1995;55:42434247),a ras farnesyl transferase inhibitor FTI276 has been shown toselectively block tumor growth in nude mice of a human lung carcinomawith K-ras mutation and p53 deletion. In yet another report, dailyadministration of a ras farnesyl transferase inhibitor L-744,832 causedtumor regression of mammary and salivary carcinomas in ras transgenicmice (Kohl et al., Nature Med., 1995;1(8):792-748). Thus, ras farnesyltransferase inhibitors have benefit in certain forms of cancer,particularly those dependent on oncogenic ras for their growth.

[0011] It is well-known, however, that human cancer is often manifestedwhen several mutations in important genes occur, one or more of whichmutations may be responsible for controlling growth and metastases. Asingle mutation may not be enough to sustain growth but after theoccurrence of only two or three mutations, tumors can develop and grow.It is difficult, therefore, to determine which of these mutations may beprimarily driving the growth in a particular type of cancer. Thus, rasfarnesyl transferase inhibitors can have therapeutic utility in tumorsnot solely dependent on oncogenic forms of ras for their growth. Forexample, it has been shown that various ras FT-inhibitors haveantiproliferative effects in vivo against tumor lines with eitherwild-type or mutant ras (Sepp-Lorenzino, supra.). In addition, there areseveral ras-related proteins that are prenylated. Proteins such asR-Ras2/TC21 are ras-related proteins that are prenylated in vivo by bothfarnesyl transferase and geranylgeranyl transferase I (Carboni et al.,Oncogene, 1995;10: 1905-1913). Therefore, ras farnesyl transferaseinhibitors could also block the prenylation of the above proteins and,therefore, would then be useful in inhibiting the growth of tumorsdriven by other oncogenes.

[0012] With regard to the restenosis and vascular proliferativediseases, it has been shown that inhibition of cellular ras preventssmooth muscle proliferation after vascular injury in vivo (Indolfi C. etal., Nature Med., 1995;1(6):541-545). This report definitively supportsa role for farnesyl transferase inhibitors in this disease, showinginhibition of accumulation and proliferation of vascular smooth muscle.

SUMMARY OF THE INVENTION

[0013] This invention provides certain 5-substituted tetralones ofFormulas I, II, III, and IV that are useful for treating and preventinguncontrolled or abnormal proliferation of tissues, such as cancer,atherosclerosis, restenosis, psoriasis, and endometriosis. Specifically,the present invention relates to compounds that inhibit the farnesyltransferase enzyme. The compounds also inhibit amyloidoses, and are thususeful to treat conditions caused by amyloidoses, such as Alzheimer's'disease. The compounds are readily synthesized and can be administeredby a variety of routes, including orally and parenterally.

[0014] The compounds of Formula I and Formula II are a sub-genus of thegenus disclosed in WO 98/34921, which is PCT Application No.PCT/US98/03025. Surprisingly, the 5-substituted tetralones of thepresent invention have shown unexpected potency as inhibitors of thefarnesyl transferase enzyme. Further, substitution at the 4 or,preferably, 5-position has also provided compounds with unexpectedpotency as farnesyl transferase inhibitors.

[0015] The present invention provides a compound of Formula I

[0016] wherein:

[0017] W is CH₂ or CH₂CH₂;

[0018] R³ is hydrogen, C₁-C₆ alkyl, phenyl, or substituted phenyl;

[0019] R^(3a) is hydrogen or C₁-C₆ alkyl;

[0020] provided that R³ and R^(3a) cannot both be hydrogen;

[0021] further provided that when R³ is phenyl or substituted phenylthat R^(3a) is hydrogen;

[0022] X is halogen, amino, C₁-C₆ alkyl, C₂-C₆ alkenyl, aryl,substituted aryl, heteroaryl, arylalkyl, substituted arylalkyl,heteroarylalkyl, substituted heteroarylalkyl, —CH₂OR⁶, —CH₂NR⁶R^(6a),—CH₂SR⁶, or —CH₂CH₂CO₂R⁶;

[0023] R⁶ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, phenyl, benzyl, C₃-C₆cycloalkyl, or substituted phenyl;

[0024] R^(6a) is hydrogen or C₁-C₆ alkyl;

[0025] Y is O or S;

[0026] R⁵ is hydrogen, C₁-C₆ allyl, or amino; and

[0027] pharmaceutically acceptable salts, esters, amides, and prodrugsthereof, provided that the compound is not

[0028]5-[(Diisobutylamino)-methyl]-6-(imidazol-1-yl-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one;

[0029]5-Amino-6-((S)-imidazol-1-ylmethyl-2-methyl-propoxy)-3,4-dihydro-2H-napthalen-1-one;

[0030]5-(3,4-Dichloro-phenylsulfanylmethyl)₆-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one;

[0031]Cyclopentylsulfanylmethyl-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one;

[0032]6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-(isopropylamino-methyl)-3,4-dihydro-2H-napthalen-1-one;

[0033]5-Biphenyl-3-yl-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one;

[0034]6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-phenyl-3,4-dihydro-2H-napthalen-1-one;

[0035]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-prop-2-enyl-2,3,4-trihydronaphthalen-1-one;or

[0036]5-Bromo-6-(2-imidazol-1-yl-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one.

[0037] The present invention also provides a compound of Formula II

[0038] wherein:

[0039] y is 0, 1, 2, or 3;

[0040] R⁷ is C₁-C₆ alkyl, C₂-C₆ alkenyl, alkoxy, —O—(C₃-C₆)cycloalkyl,—O—(C₂-C₆)alkenyl, halogen, —NH₂, —CO₂H, —CO₂-alkyl, —O-phenyl,—O-substituted phenyl, —O-benzyl, —S—(C₁-C₆)alkyl, —S—(C₃-C₆)cycloalkyl,—S-phenyl, —S-substituted phenyl, —NH-phenyl, —NH-substituted phenyl,aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0041] provided that when R⁷ is —NH₂ that y is 0;

[0042] further provided that when R⁷ is phenyl that y cannot be 0; and

[0043] pharmaceutically acceptable salts, esters, amides, and prodrugsthereof, provided that the compound is not

[0044]5-Bromo-6-(2-imidazol-1-yl-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one;

[0045]5-(3,4-Dichloro-phenylsulfanylmethyl)₆-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one

[0046]Cyclopentylsulfanylmethyl-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one

[0047]5-Biphenyl-3-yl-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one;or

[0048]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-prop-2-enyl-2,3,4-trihydronaphthalen-1-one.

[0049] Additionally, the present invention provides a compound ofFormula III

[0050] wherein:

[0051] R⁹ is phenyl, substituted phenyl, heteroaryl, or C₁-C₆ alkyl;

[0052] R¹⁰ is hydrogen, C₁-C₆ alkyl, or C₁-C₆ substituted alkyl;

[0053] y is 0, 1, 2, or 3;

[0054] R¹¹ is —O-substituted alkyl, —O-aryl, —O-substituted aryl,—O-aryl-heteroaryl, —O-heteroaryl, —O-substituted heteroaryl,—O-phenyl-O—CF₃, —O-phenyl-O-phenyl, —S-aryl, —S-substituted aryl,—S-arylalkyl, —S(O)z-substituted alkyl, —S(O)z-substituted arylalkyl,—S(O)z-heteroaryl, —S(O)z-heteroarylalkyl, —S(O)z-substitutedheteroaryl, —SO-alkyl, —SO₂-alkyl, —SO-aryl, —SO₂-aryl, —SO-substitutedaryl, —SO₂-substituted aryl, —SO-arylalkyl, —SO₂-arylalkyl,—S(O)z-phenyl-CONH—R¹³, —NHSO₂—R¹⁴, —NHCO—R¹⁴, NHCO-heteroaryl-O-aryl,NHCO-heteroaryl-substituted aryl, NHCOC(substituted alkyl)NHCO₂-alkyl,—NHCO—C(substituted alkyl)amino, —NHCO₂-alkyl, —NH-aryl, —NH-substitutedaryl, —NH-heteroaryl, —NH—(CH₂)₂—O-heteroaryl, —N(CO-alkyl)substitutedaryl, -aryl-CO-alkyl,

[0055] z is 0, 1 or 2;

[0056] R¹³ is alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, orheteroarylalkyl;

[0057] R¹⁴ is aryl, substituted aryl, arylalkyl, heteroaryl,heteroarylalkyl, or substituted heteroaryl; provided that when R¹¹ is—O-aryl, —O-substituted aryl, —S-aryl, —S-arylalkyl, S-substituted aryl,—NH-aryl, or —NH-substituted aryl that the aryl is not phenyl; and

[0058] pharmaceutically acceptable salts, esters, amides, and prodrugsthereof.

[0059] Furthermore, the present invention provides a compound of theFormula IV

[0060] wherein:

[0061] y is 0, 1, 2, or 3;

[0062] R¹⁵ is lower alkyl, lower alkenyl, alkoxy, substituted alkoxy,arylalkoxy, —O-cycloalkyl, —O-alkenyl, alkylthio, hydroxy, thiol, cyano,halogen, —CF₃, —NO₂, —NH₂, —NH-alkyl, —NH-dialkyl, —NHCO-alkyl, —CO₂H,—CO₂-alkyl, —SO₃H, —O-aryl, —O-substituted aryl, —O-heteroaryl,—O-substituted heteroaryl, —S-alkyl, —S-substituted alkyl,—S-cycloalkyl, —S-aryl, —S-substituted aryl, —S-heteroaryl,—S-substituted heteroaryl, —SO₂NH₂, —SO₂NH-alkyl, —SO-aryl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-alkyl, —SO₂-heteroaryl, —SO₂-substitutedheteroaryl, —NHSO₂-aryl, —NHCO-aryl, —NHCO-heteroaryl, —NHCO₂-alkyl,—NH-aryl, —NH-substituted aryl, aryl, substituted aryl, heteroaryl, andsubstituted, heteroaryl;

[0063] Y² is NR⁶, O, S, or CR¹⁷R^(17a);

[0064] R¹⁶ is hydrogen, lower alkyl, aryl, arylalkyl, heteroaryl, orcycloalkyl;

[0065] R¹⁷ and R^(17a) are each independently hydrogen, lower alkyl,lower alkenyl, cycloalkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl,substituted heterocycloalkyl, heterocyclalkylalkyl, substitutedheterocycloalkylalkyl, halogen, trifluoromethyl, —OR¹⁹, —NR¹⁹R^(19a),NHSO₂R¹⁹, —S(O)_(z)R¹⁹, —SO₂NHR¹⁹, —OCOR¹⁹, —CH₂OR¹⁹, —CH₂NR¹⁹R^(19a),—CH₂S(O)_(z)R¹⁹, —CH₂NHSO₂R¹⁹, —CH₂S(O)_(z)R¹⁹, —CH₂SO₂NHR¹⁹, or—CH₂OCOR¹⁹;

[0066] R¹⁹ and R^(19a) are each independently hydrogen, lower alkyl,aryl, arylalkyl, heteroaryl, or cycloalkyl;

[0067] provided that one of A, B, and C is N while the other two are CH;and

[0068] pharmaceutically acceptable salts, esters, amides, and prodrugsthereof.

[0069] The present invention also provides a pharmaceutically acceptablecomposition that comprises a compound of Formulas I-IV and apharmaceutically acceptable carrier.

[0070] The present invention also provides a method of treating orpreventing restenosis, the method comprising administering to a patienthaving restenosis or at risk of having restenosis a therapeuticallyeffective amount of a compound of Formulas I-IV.

[0071] The present invention also provides a method of treating cancer,the method comprising administering to a patient having cancer atherapeutically effective amount of a compound of Formulas I-IV. In apreferred embodiment of the method of treating cancer, the cancer islung, colon, pancreatic, thyroid, or bladder cancer.

[0072] The present invention also provides a method of treatingatherosclerosis, the method comprising administering to a patient havingatherosclerosis a therapeutically effective amount of a compound ofFormulas I-IV.

[0073] Also provided is a method of treating or preventing restenosis oratherosclerosis or treating cancer, the method of comprisingadministering to a patient having restenosis or atherosclerosis, or atrisk of having restenosis or atherosclerosis, or having cancer atherapeutically effective amount of a compound of Formulas I-IV.

[0074] The present invention also provides a method of treatingneurofibromin benign proliferative disorder, blindness related toretinal vascularization, hepatitis delta and related viruses, psoriasis,benign prostatic hypertrophy and polycystic kidney disease, the methodcomprising administering to a patient having such a condition atherapeutically effective amount of a compound of Formulas I-IV.

[0075] In addition, the present invention provides the use of a compoundof Formulas I-IV, or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for treating or preventing any of thediseases or disease states mentioned above.

[0076] Furthermore, the present invention provides the use of a compoundof Formulas I-IV, or a pharmaceutically acceptable salt thereof fortreating or preventing any of the diseases or disease states mentionedabove.

DETAILED DESCRIPTION OF THE INVENTION

[0077] The novel compounds encompassed by the instant invention arethose described by the general Formulas I-IV set forth above, and thepharmaceutically acceptable salts, esters, amides, and prodrugs thereof.

[0078] In addition to the compounds of Formulas I-IV, the presentinvention encompasses compounds of Formula V-VIII. The present inventionprovides compounds of Formula V:

[0079] wherein:

[0080] —is a bond or absent;

[0081] W is NR^(1′), CR^(1′)R^(1′a), CR^(1′)R^(1′a)CR^(2′)R^(2′a),CR^(1′)R^(1′a)NR^(2′) or CR^(1′)R^(1′a) O;

[0082] R^(1′), R^(1′a), R^(2′) and R^(2′a) independently representhydrogen, lower alkyl, lower alkenyl, cycloalkyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heterocycloalkyl, substituted heterocycloalkyl, heterocycloalkylalkyl,substituted heterocycloalkylalkyl, halogen, trifluoromethyl, —OR^(6′),—NR^(6′)R^(6′a), NHSO₂R^(6′), —S(O)_(z′)R^(6′), —SO₂NHR^(6′),—OCOR^(6′), —CH₂OR^(6′), —CH₂NR^(6′)R^(6′a), —CH₂S(O)_(z′)R^(6′),—CH₂NHSO₂R^(6′), —CH₂S(O)_(z′)R^(6′), —CH₂SO₂NHR^(6′), or —CH₂OCOR^(6′);

[0083] z′ is 0, 1, or 2;

[0084] V′ is hydrogen, halogen, lower alkyl, C₁-C₆ lower alkoxy,hydroxy, amino or nitro;

[0085] R³′, R^(3′a), R^(4′), and R^(4′a) independently are hydrogen,halogen, lower alkyl, lower alkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, arylalkyl, substituted arylalkyl,heterocycloalkyl, substituted heterocycloalkyl, heterocycloalkylalkyl,substituted heterocycloalkylalkyl, heteroarylalkyl, or substitutedheteroarylalkyl;

[0086] X′ is hydrogen, halogen, amino, substituted amino, lower alkyl,substituted lower alkyl, lower alkenyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,arylalkyl, substituted arylalkyl, heterocycloalkyl, substitutedheterocycloalkyl, heterocycloalkylalkyl, substitutedheterocycloalkylalkyl, heteroarylalkyl, substituted heteroarylalkyl,—OR^(6′), —NR^(6′)R^(6′a), NHSO₂R^(6′), —S(O)_(z′)R^(6′), —SO₂NHR^(6′),

[0087]  —OCOR^(6′), —CH₂OR^(6′), —CH₂NR^(6′)R^(6′a),—CH₂S(O)_(z′)R^(6′), —CH₂NHSO₂R^(6′), —CH₂S(O)_(z′)R^(6′),—CH₂SO₂NHR^(6′), or —CH₂OCOR^(6′);

[0088] R^(6′) and R^(6′a) independently represent hydrogen, lower alkyl,aryl, arylalkyl, heteroaryl or cycloalkyl;

[0089] Y′ is NR^(6′), O, S, or CR^(1′)R^(1′a); and

[0090] R^(5′) is hydrogen, lower alkyl or substituted lower alkyl.

[0091] In addition to the compounds of Formula V, the inventionencompasses compounds of Formula VI:

[0092] wherein R^(2′) and R^(2′a) are independently hydrogen orfluorine; y′ is 0, 1, 2, or 3; and R^(7′) is lower alkyl, lower alkenyl,alkoxy, substituted alkoxy, arylalkoxy, —O-cycloalkyl, —O-alkenyl,alkylthio, hydroxy, thiol, cyano, halogen, —CF₃, —NO₂, —NH-alkyl,—NH-dialkyl, —NHCO-alkyl, —CO₂H, —CO₂-alkyl, —SO₃H, —O-aryl,—O-substituted aryl, —O-heteroaryl, —O-substituted heteroaryl, —S-alkyl,—S-substituted alkyl, —S-cycloalkyl, —S-aryl, —S-substituted aryl,—S-heteroaryl, —S-substituted heteroaryl, —SO₂NH₂, —SO₂NH-alkyl,—SO-aryl, —SO₂-aryl, —SO₂-substituted aryl, —SO₂-alkyl, —SO₂-heteroaryl,—SO₂-substituted heteroaryl, NHSO₂-aryl, —NHCO-aryl, —NHCO-heteroaryl,—NHCO₂-alkyl, —NH-aryl, —NH-substituted aryl, aryl, substituted aryl,heteroaryl, and substituted heteroaryl.

[0093] Preferred compounds of Formula VI are those where y′ is 0, 1, or2.

[0094] The invention also encompasses compounds of Formula VII:

[0095] wherein y′ and R^(7′) are as defined above for Formula VI.

[0096] Preferred compounds of Formula VII are those where y′ is 1 or 2,and R^(7′) is lower aryl or heteroaryl.

[0097] The invention further encompasses compounds of the Formula VIII:

[0098] wherein Y′ is as defined above for Formula V; y′ and R^(7′) areas defined above for Formula VI; and one of A′, B′, and C′ is N whilethe other two are CH.

[0099] Preferred compounds of Formula VIII are those where Y′ is O or S,y′ is 1 or 2, and R^(7′) is lower alkyl, aryl or lower alkenyl.

[0100] The terms “alkyl,” “lower alkyl,” or “(C₁-C₁₀)-alkyl” mean astraight or branched hydrocarbon having from 1 to 10 carbon atoms andincludes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like. Thealkyl group can also be substituted (and thus may be referred to as“substituted alkyl”) with one or more of the substituents listed belowfor aryl. The term “(C₁-C₁₀)-alkyl” includes within its definition theterm “C₁-C₆ alkyl”.

[0101] The term “cycloalkyl” or “(C₃-C₇)-cycloalkyl” means a saturatedhydrocarbon ring which contains from 3 to 7 carbon atoms, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and thelike. The term “(C₃-C₇)-cycloalkyl” includes within its definition theterm “C₃-C₆ cycloalkyl”.

[0102] By “alkoxy,” “lower alkoxy,” or “(C₁-C₁₀)-alkoxy” in the presentinvention is meant straight or branched chain alkoxy groups having 1-10carbon atoms, such as, for example, methoxy, ethoxy, propoxy,isopropoxy, n-butoxy, sec-butoxy, tertbutoxy, pentoxy, isopentoxy,neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.

[0103] The alkoxy group can also be substituted (and thus may bereferred to as “substituted alkoxy”) with one or more of thesubstituents listed below for aryl.

[0104] The term “alkenyl,” “lower alkenyl,” or “(C₂-C₁₀)-alkenyl” meansa straight or branched hydrocarbon radical having from 1-10 carbon atomsand 1-2 double bonds and includes, for example, allyl,3-methyl-but-2-enyl, 2-methyl-but-2-enyl, geranyl, and the like. Theterm “(C₂-C₁₀)-alkenyl” includes within its definition the term “C₂-C₆alkenyl”.

[0105] The term “alkynyl” or “lower alkynyl” means a straight orbranched hydrocarbon radical having from 2-10 carbon atoms and at leastone triple bond and includes, for example, acetylene.

[0106] The term “aryl” means an unsubstituted aromatic carbocyclic grouphaving a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), ormultiple condensed rings in which at least one is aromatic (e.g.,1,2,3,4-tetrahydronaphenyl, naphenyl, anthryl, or phenanthryl). The term“substituted aryl” means an aryl substituted by 1 to 4 substituentsselected from alkyl, —O-alkyl, —S-alkyl, —OH, —SH, —CN, carboxy,guanidino, halogen, 1,3-dioxolanyl, —CF₃, —NO₂, —(CH₂)_(m)—NHCO-alkyl,—(CH₂)_(m)—N(alkyl)CO-alkyl —CONH₂, —CON-dialkyl-SO₃H, —(CH₂)_(m)CO₂H,—(CH₂)_(m)CO₂-alkyl, —(CH₂)_(m)SO₃H, —(CH₂)_(m)NH₂, —(CH₂)_(m)NH-alkyl,—(CH₂)_(m)—N-dialkyl, —CH₂)_(m)PO₃H₂,

[0107] —(CH₂)_(m)PO₃(alkyl)₂, —(CH₂)_(m)SO₂NH₂, —(CH₂)_(m)SO₂NH-alkylwherein alkyl is defined as above and m is 0, 1, 2, 3, 4 or 5, and

[0108] The term “arylalkyl” means an alkyl moiety (as defined above)substituted with an aryl moiety (also as defined above). The term“substituted arylalkyl” means an arylalkyl moiety substituted by 1 to 3substitutents selected from the group as defined above for “substitutedaryl.”

[0109] By halogen in the present invention is meant fluorine, bromine,chlorine, and iodine.

[0110] By heteroaryl (aromatic heterocycle) in the present invention ismeant one or more aromatic ring systems of 5-, 6-, or 7-membered ringscontaining at least one and up to four hetero atoms selected fromnitrogen, oxygen, or sulfur. Such heteroaryl groups include, forexample, thienyl, furanyl, thiazolyl, imidazolyl, (is)oxazolyl, pyridyl,pyrimidinyl, (iso)quinolinyl, naphthyridinyl, benzimidazolyl, andbenzoxazolyl. The term “substituted heteroaryl” means a heteroarylsubstituted by 1 to 3 substituents selected from the group as foundabove for “substituted aryl”.

[0111] The term “heteroarylalkyl” means an alkyl moiety (as definedabove) substituted with an heteroaryl moiety (also as defined above).The term “substituted heteroarylalkyl means a heteroarylalkylsubstituted by 1 to 3 substituents selected from the group as definedabove for “substituted aryl.”

[0112] The symbol “−” means a bond.

[0113] The following abbreviations are used in the application. HPLCHigh pressure liquid chromatography CI-MS Chemical Ionization MassSpectrometry mp Melting point RT Room temperature THF TetrahydrofuranAPCI-MS Atmospheric pressure chemical ionization mass spectrometry decDecomposes HOAc Acetic acid CDI Carbonyl diimidazole CHCl₃ ChloroformDCM Dichloromethane DEAD Diethyl azodiacarboxylate DMAP4-dimethylaminopyridine DMF N,N'-Dimethylformamide DMSO dimethylsulfoxide EtOAc Ethyl acetate EtOH Ethanol Et₂O Diethyl ether Et₃NTriethylamine HATUO-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumhexafluorophosphate HCl Hydrochloric acid H₂O₂ Hydrogen peroxide H₂SO₄Sulfuric acid KOH Potassium hydroxide mCPBA m-chloroperoxybenzoic acidMeCN Acetonitrile MeOH Methanol NaH Sodium hydride NaOH Sodium hydroxideNaHCO₃ Sodium bicarbonate NBS N-bromosuccinimide iPrOH iso-Propanol pTSAp-toluenesulfonic acid TFAA Trifluoroacetic acid Tf₂OTrifluoromethanesulfonic anhydride Boc tertiary Butyloxycarbonyl TsTosylate Ph₃P Triphenylphosphine

[0114] The term “patient” means all animals, preferably mammals,including humans. Examples of patients include humans, cows, dogs, cats,goats, sheep, and pigs.

[0115] The term “treating” for purposes of the present invention refersto prophylaxis or prevention, amelioration or elimination of a namedcondition once the condition has been established.

[0116] A “therapeutically effective amount” is an amount of a compoundof the present invention that when administered to a patient amelioratesa symptom of a disease state, such as restenosis, cancer, oratherosclerosis, or prevents a disease, such as restenosis. Atherapeutically effective amount of a compound of the present inventioncan be easily determined by one skilled in the art by administering aquantity of a compound to a patient and observing the result. Inaddition, those skilled in the art are familiar with identifyingpatients having the diseases or disease states treated or prevented by acompound of the present invention, such as cancer, restenosis, oratherosclerosis or patients who are at risk of having restenosis.

[0117] The term “cancer” includes, but is not limited to, the followingcancers: breast, ovary, uterine, fallopian tubes, endometrium, vagina,vulva, cervix, prostate, testis, penis, esophagus, glioblastoma,neuroblastoma, stomach, skin, keratoacanthoma, cutaneous or intraocularmelanoma, lung, endocrine system, thyroid gland, parathyroid gland,adrenal gland, sarcoma of soft tissue, epidermoid carcinoma, large cellcarcinoma, adenocarcinoma, bone, colon, adenocarcinoma, adenoma,pancreas, adenocarcinoma, thyroid, follicular carcinoma,undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma,sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidneycarcinoma, urethra, renal cell carcinoma, carcinoma of the renal pelvis,myeloid disorders, lymphoid disorders, Hodgkins, hairy cells, buccalcavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine,colon-rectum, cancer of the anal region, large intestine, rectum, cancerof the head or neck, brain and central nervous system, neoplasms of thecentral nervous system (CNS), primary CNS lymphona, spinal axis tumors,brain stem glioma, pituitary adenoma, chronic or acute leukemia, andlymphocytic lymphomas.

[0118] The term “pharmaceutically acceptable salts, esters, amides, andprodrugs” as used herein refers to those carboxylate salts, amino acidaddition salts, esters, amides, and prodrugs of the compounds of thepresent invention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of patients without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use,as well as the zwitterionic forms, where possible, of the compounds ofthe invention. The term “salts” refers to the relatively non-toxic,inorganic and organic acid addition salts of compounds of the presentinvention. These salts can be prepared in situ during the finalisolation and purification of the compounds or by separately reactingthe purified compound in its free base form with a suitable organic orinorganic acid and isolating the salt thus formed. Representative saltsinclude the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate,acetate, oxalate, valerate, oleate, palmitate, stearate, laurate,borate, benzoate, lactate, phosphate, tosylate, citrate, maleate,fumarate, succinate, tartrate, naphenylate methylate, glucoheptonate,lactobionate and laurylsulphonate salts, and the like. These may includecations based on the alkali and alkaline earth metals, such as sodium,lithium, potassium, calcium, magnesium and the like, as well asnon-toxic ammonium, quaternary ammonium, and amine cations including,but not limited to ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine,and the like. (See, for example, Berge S. M. et al., “PharmaceuticalSalts,” J. Pharm. Sci., 1977;66:1-19 which is incorporated herein byreference.)

[0119] Examples of pharmaceutically acceptable, non-toxic esters of thecompounds of this invention include C₁-C₆ alkyl esters wherein the alkylgroup is a straight or branched chain. Acceptable esters also includeC₅-C₇ cycloalkyl esters as well as arylalkyl esters such as, but notlimited to benzyl. C₁-C₄ alkyl esters are preferred. Esters of thecompounds of the present invention may be prepared according toconventional methods.

[0120] Examples of pharmaceutically acceptable, non-toxic amides of thecompounds of this invention include amides derived from ammonia, primaryC₁-C₆ alkyl amines and secondary C₁-C₆ dialkyl amines wherein the alkylgroups are straight or branched chain. In the case of secondary aminesthe amine may also be in the form of a 5- or 6-membered heterocyclecontaining one nitrogen atom. Amides derived from ammonia, C₁-C₃ alkylprimary amines and C₁-C₂ dialkyl secondary amines are preferred. Amidesof the compounds of the invention may be prepared according toconventional methods.

[0121] The term “prodrug” refers to compounds that are rapidlytransformed in vivo to yield the parent compound of the above formulae,for example, by hydrolysis in blood. A thorough discussion is providedin T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol.14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are hereby incorporated byreference.

[0122] Representative compounds of the invention are shown below inTable 1. TABLE 1

 1  6

 17

 21

 24

 35

 40

 47

 56

 63

 76

117

 63a

[0123] Representative compounds of the present invention, which areencompassed by Formulas I-VIII include, but are not limited to thecompounds in Table 1 and their pharmaceutically acceptable acid or baseaddition salts, or amide or prodrugs thereof.

[0124] Preferred compounds of Formula I are those wherein W is CH₂CH₂; Yis O; R³ is aryl; R^(3a) is hydrogen; R⁵ is hydrogen; and X isarylalkyl, substituted arylalkyl, heteroarylalkyl, substitutedheteroarylalkyl, —CH₂OR⁶, —CH₂NR⁶R^(6a), or —CH₂SR⁶.

[0125] Preferred compounds of Formula II are those wherein R⁷ is—O-phenyl, —O-substituted phenyl, —O-benzyl, —S—(C₁-C₆)alkyl,—S—(C₃-C₆)cycloalkyl, —S-phenyl, —S-substituted phenyl, —NH-phenyl,—NH-substituted phenyl, aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl.

[0126] Preferred compounds of Formula III are those wherein R⁹ is phenylor heteroaryl; R¹⁰ is hydrogen; y is 0 or 1; and R¹¹ isS(O)z-substituted alkyl, —S(O)_(z)-substituted arylalkyl,—S(O)z-heteroaryl, —S(O)z-heteroarylalkyl, —S(O)z-substitutedheteroaryl, —SO₂-alkyl, —SO₂-aryl, —SO₂-substituted aryl,—SO₂-arylalkyl, —S(O)z-phenyl-CONH—R¹³, —NHSO₂—R¹⁴, or —NHCO—R¹⁴;preferably R¹¹ is —S(O)z-phenyl-CONH—R¹³, —NHSO₂—R¹⁴, or —NHCO—R¹⁴; andmore preferably R¹¹ is —NHCO—R¹⁴; and R¹⁴ is heteroaryl.

[0127] Preferred compounds of Formula IV are those wherein A is N whileB and C are CH; B is N while A and C are CH; Y² is O; y is 0, 1, or 2;preferably, 0 or 1; R ¹⁵ is —O-substituted aryl, —O-heteroaryl,—O-substituted heteroaryl, —S-alkyl, —S-substituted alkyl,—S-cycloalkyl, —S-aryl, —S-substituted aryl, —S-heteroaryl,—S-substituted heteroaryl, —SO₂NH₂, —SO₂NH-alkyl, —SO-aryl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-alkyl, —SO₂-heteroaryl, —SO₂-substitutedheteroaryl, —NHSO₂-aryl, —NHCO-aryl, —NHCO-heteroaryl, —NHCO₂-alkyl,—NH-aryl, —NH-substituted aryl, aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl; preferably, R¹⁵ is aryl, heteroaryl, —SO₂-alkyl,—SO₂-heteroaryl, or —NHCO-heteroaryl; and more preferably, R¹⁵ is—SO₂-alkyl, —SO₂-heteroaryl, or —NHCO-heteroaryl.

[0128] Illustrative of compounds encompassed by Formula I include thefollowing list of compounds. This list is meant to be representativeonly and is not intended to limit the scope of the invention in any way:

[0129]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(phenylthiomethyl)-2,3,4-trihydronaphthalen-1-one(Compound 1);

[0130] Methyl2-{[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphenyl]methylthio}benzoate(Compound 4);

[0131]2-{[2-((1S)-2-Imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphenyl]methylthio}benzoicacid (Compound 5);

[0132]6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-isopropylsulfanylmethyl-2,3,4-trihydronaphthalen-1-one(Compound 6);

[0133]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(phenylamino)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 11);

[0134] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(methylphenylamino)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 12);

[0135] Methyl4-({[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo(6,7,8-trihydronaphenyl)]methyl}methylamino)benzoate(Compound 13);

[0136]4-({[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo(6,7,8-trihydronaphenyl)]methyl}methylamino)benzoicacid, 2,2,2-trifluoroacetic acid (Compound 14);

[0137]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(methylethoxy)methyl]-2,3,4-trihydronaphthalen-1-onehydrochloride (Compound 15);

[0138]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(phenylmethoxy)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 16);

[0139]6-((1S)-2-Imidazolyl-phenylethoxy)-5-(cyclopentyloxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 17);

[0140]6-((1S)-2-imidazolyl-1-phenylethoxy)-5-(prop-2-enyloxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 18);

[0141]6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-isobutoxymethyl-3,4-dihydro-2H-naphthalen-1-one(Compound 19a);

[0142]6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-propoxymethyl-3,4-dihydro-2H-naphthalen-1-one(Compound 19b);

[0143]5-(1-Ethyl-propoxymethyl)-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one(Compound 19c);

[0144](±)5-sec-Butoxymethyl-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one(Compound 19d);

[0145]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-phenylethyl)-2,3,4-trihydronaphthalen-1-one(Compound 20);

[0146]5-(2H-Benzo[d]1,3-dioxolan-5-yl)-6-((1S)-2-imidazolyl-1-phenylethoxy)2,3,4-trihydronaphthalen-1-one(Compound 21);

[0147]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(3-chlorophenyl)-2,3,4-trihydronaphthalen-1-one(Compound 22);

[0148]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-naphthyl)-2,3,4-trihydronaphthalen-1-one(Compound 23);

[0149]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-(2-pyridyl)ethyl)-2,3,4-trihydronaphthalen-1-one(Compound 24);

[0150]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-(4-pyridyl)ethyl)-2,3,4-trihydronaphthalen-1-one(Compound 26);

[0151](S)-6-(-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(2-pyridin-3-yl-ethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 26b);

[0152](S)-6-(-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(2-pyridin-3-yl-ethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 26c);

[0153] Methyl4-{2-[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphenyl]ethyl}benzoate(Compound 27);

[0154] Methyl4-{2-[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphenyl]ethyl}benzoate(Compound 28);

[0155]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[2-(4-fluorophenyl)ethyl]-2,3,4-trihydronaphthalen-1-one(Compound 30);

[0156] Methyl3-[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphenyl]propanoate(Compound 31);

[0157]3-[2-((1S)-2-Imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphenyl]propanoicacid (Compound 32);

[0158]4-{[2-((1S)-2-Imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphenyl]methyl}benzenecarbonitrile(Compound 33);

[0159]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-bromo-2,3,4-trihydronaphthalen-1-one(Compound 34);

[0160]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(3-thienyl)-2,3,4-trihydronaphthalen-1-one(Compound 35);

[0161]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(3-furyl)-2,3,4-trihydronaphthalen-1-one,2,2,2-trifluoroacetic acid (Compound 36);

[0162]5-Amino-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one(Compound 37a);

[0163]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-phenylpropyl)-2,3,4-trihydronaphthalen-1-one(Compound 44);

[0164]6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(2-thiophen-3-yl-ethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 44a);

[0165]6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(3-phenyl-propyl)-3,4-dihydro-2H-naphthalen-1-one(compound 44b);

[0166]6-((1S)-2-imidazolyl-1-phenylethoxy)-5-benzyl-2,3,4-trihydronaphthalen-1-one(Compound 45);

[0167](6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-propyl-2,3,4-trihydronaphthalen-1-one(Compound 53);

[0168]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-methylprop-2-enyl)-2,3,4-trihydronaphthalen-1-one(Compound 54);

[0169]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-methylpropyl)-2,3,4-trihydronaphthalen-1-one(Compound 55);

[0170] 5-((1S)-2-Imidazolyl-1-phenylethoxy)-4-prop-2-enylindan-1-one(Compound 56);

[0171]6-[2-(1H-Imidazol-1-yl)-1,1-dimethylethoxy]-5-(2-phenylethyl)-3,4-dihydro-1(2H)-naphthalenone(Compound 58a);

[0172]6-((1S)-2-imidazolyl-1-phenylethylthio)-5-propyl-2,3,4-trihydronaphthalen-1-one(Compound 62);

[0173]6-((1S)-2-Imidazolyl-1-phenylethylthio)-5-(2-phenylethyl)-2,3,4-trihydronaphthalen-1-one(Compound 63);

[0174](S)-6-(1-imidazol-1-ylmethyl-2-methyl-propoxy)-5-(2-pyridin-4-yl-ethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 63i);

[0175](S)-6-[-1-(4-Fluoro-phenyl)-2-imidazol-1-yl-1-ethoxy]-5-(2-pyridin-4-yl-ethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 63k);

[0176]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(methoxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 64);

[0177]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(methoxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 65);

[0178]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(phenoxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 66);

[0179]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[3-(tert-butyl)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one(Compound 67);

[0180] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[2-(methylethyl)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one (Compound 68);

[0181]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(3-chlorophenoxy)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 69);

[0182] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[2-methyl-5-(methylethyl)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one (Compound 70);

[0183] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(3,5-dimethoxyphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 71);

[0184]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[4-(methylethyl)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one(Compound 72);

[0185]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-5,6,7,8-tetrahydro-naphenyloxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 73);

[0186] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[3-(methylethyl)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one (Compound 74);

[0187] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[2-(methylethoxy)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one (Compound 77);

[0188] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-ethoxyphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 78);

[0189] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-ethoxyphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 79);

[0190]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(3-ethylphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 80);

[0191] Methyl2-{[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphenyl]methoxy}benzoate(Compound 81);

[0192]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-ethylphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 84);

[0193]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-naphenyloxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 85);

[0194]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-chloro-5-methylphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 86);

[0195] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[2-(methylpropyl)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one (Compound 87);

[0196] Methyl3-{[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]methoxy}benzoate(Compound 88);

[0197] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2,4,6-trimethylphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 89);

[0198] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[4-(methylpropyl)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one (Compound 90);

[0199] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[4-(trifluoromethyl)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one (Compound 91);

[0200]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2H-benzo[d]1,3-dioxolan-5-yloxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 92);

[0201]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2H-benzo[d]1,3-dioxolan-5-yloxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 93);

[0202]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(8-quinolyloxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 95)

[0203] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-chlorophenoxy)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 98);

[0204] 6-((1S)-2-imidazolyl-1-phenylethoxy)-5-[(3-methylphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 99);

[0205] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-methylphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 100);

[0206]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-fluorophenoxy)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 101);

[0207]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(3-fluorophenoxy)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 102);

[0208]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-fluorophenoxy)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 103);

[0209]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(naphenyloxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 104);

[0210] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(3-methoxyphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 105);

[0211] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-chlorophenoxy)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 106);

[0212]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(6-quinolyloxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 108);

[0213] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-bromophenylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 109);

[0214] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-fluorophenylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 110);

[0215]N-(4-{[2-((1S)-2-Imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphenyl]methylthio}phenyl)acetamide(Compound 111);

[0216] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-hydroxyphenylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 112);

[0217] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-methylphenylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 113);

[0218] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-methylpropylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 114);

[0219]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(cyclohexylthiomethyl)-2,3,4-trihydronaphthalen-1-one(Compound 117);

[0220] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-bromophenylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 130);

[0221] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-chlorophenylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 131);

[0222] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2,6-dichlorophenylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 132);

[0223] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-methoxyphenylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 133);

[0224] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-methylphenylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 134);

[0225] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-methoxyphenylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 135);

[0226] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-nitrophenylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 137);

[0227] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(3-methoxyphenylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 138);

[0228] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-chlorophenylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 139);

[0229]2-{[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-napthalen-1-ylmethyl]-amino}-benzonitrile(Compound 149);

[0230]5-[(4-Bromo-phenylamino)-methyl]-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one(Compound 150);

[0231]5-[(4-Fluoro-phenylamino)-methyl]-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one(Compound 151);

[0232]5-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylamino)-methyl]-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one(Compound 152);

[0233] Methyl4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoate(Compound 157);

[0234] Methyl3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoate(Compound 158);

[0235]4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicAcid. (Compound 162); and

[0236]3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicAcid. (Compound 163).

[0237] Illustrative of compounds encompassed by Formula III include thefollowing list of compounds. This list is meant to be representativeonly and is not intended to limit the scope of the invention in any way:

[0238]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(phenylsulfinyl)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 2);

[0239]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(phenylsulfonyl)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 3);

[0240]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[(methylethyl)sulfonyl]methyl}-2,3,4-trihydronaphthalen-1-one(Compound 7);

[0241]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(4-pyridylthiomethyl)-2,3,4-trihydronaphthalen-1-one(Compound 8);

[0242]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-pyridylthiomethyl)-2,3,4-trihydronaphthalen-1-one(Compound 9);

[0243] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-pyridylsulfonyl)methyl]-2,3,4-trihydronaphthalen-1-one hydrochloride (Compound 10);

[0244]6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(naphthalen-1-ylsulfanylmethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 10a);

[0245][2-(2-Imidazol-1-yl-1(S)-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethylsulfanyl]-aceticacid methyl ester (Compound 10b);

[0246]5-(3,4-Dichloro-benzylsulfanylmethyl)-6-((1S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one(Compound 10c);

[0247](S)-6-{2-[2-(Hydroxymethyl)-1H-imidazol-1-yl]-1-phenylethoxy}-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone(Compound 10d);

[0248]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-methoxyethoxy)-methyl]-2,3,4-trihydronaphthalen-1-one(Compound 19);

[0249]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[2-(1-oxy(2-pyridyl))ethyl]-2,3,4-trihydronaphthalen-1-one(Compound 25);

[0250](S)-6-(2-Imidazol-1-y-1-phenyl-ethoxy)-5-[2-(1-oxy-pyridin-4-yl)-ethyl]-3,4-dihydro-2H-naphthalen-1-one(Compound 26a);

[0251](4-{2-[2-((1S)-2-Imidazolyl-1-phenylethoxy)-5-oxo(6,7,8-trihydronaphenyl)]ethyl}phenyl)-N-methylcarboxamide(Compound 29);

[0252]N-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-benzenesulfonamide(Compound 38);

[0253]N-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-1-phenyl-methanesulfonamide(Compound 39);

[0254]N-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-2-pyridin-2-yl-acetamide(Compound 39a);

[0255] Pyridine-2-carboxylic acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide(Compound 40);

[0256] Isoquinoline-1-carboxylic acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide(Compound 40a);

[0257] Isoquinoline-3-carboxylic acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide(Compound 40b);

[0258] Pyrazine-2-carboxylic acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide(Compound 40c);

[0259] 5-(4-Chloro-phenyl)-oxazole-4-carboxylic acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide(Compound 40d);

[0260]N-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-2-chloro-nicotinamide(Compound 40e);

[0261]N-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-2-phenoxy-nicotinamide(Compound 40f);

[0262] Quinoline-8-carboxylic acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide(Compound 40g)

[0263][2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-carbamicacid tert-butyl ester (Compound 41);

[0264]N-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-benzenesulfonamide(Compound 42);

[0265]N-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-4-methoxy-benzenesulfonamide(Compound 42a);

[0266]2,4-Difluoro-N-[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-benzenesulfonamide;compound with trifluoro-acetic acid (Compound 42b);

[0267]2-{[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-sulfamoyl}-benzoicacid methyl ester; compound with trifluoro-acetic acid (Compound 42c);

[0268] 2,5-Dichloro-thiophene-3-sulfonic acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-amide;compound with trifluoro-acetic acid (Compound 42d);

[0269]3-Chloro-N-[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-benzenesulfonamide;compound with trifluoro-acetic acid (Compound 42e);

[0270] Naphthalen-2-sulfonic acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-amide;compound with trifluoro-acetic acid (Compound 42f);

[0271]N-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-C-phenyl-methanesulfonamide(Compound 42g);

[0272] Pyridine-2-carboxylic acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-amide(Compound 42h);

[0273]N-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-benzamide(Compound 42i);

[0274]((S)-1-{[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-carbamoyl}-3-methylsulfanyl-propyl)carbamicacid tert-butyl ester (Compound 42j);

[0275](S)-2-Amino-N-[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-4-methylsulfanyl-butyramide(Compound 42k);

[0276]2-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-isoindole-1,3-dione(Compound 43);

[0277] -356-((1S)-2-Imidazolyl-1-phenylethoxy)-5-phenoxy-2,3,4-trihydronaphthalen-1-one(Compound 46);

[0278]6-((S)-1-Imidazol-1-ylmethyl-2-methyl-propoxy)-5-(propane-2-sulfonylmethyl)-3,4-dihydro-2H-napthalen-1-one(Compound 63g);

[0279] Isoquinoline-1-carboxylic acid[2-((S)-1-imidazol-1-ylmethyl-2-methyl-propoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide(Compound 63h);

[0280](S)-6-[-1-(2,4-Difluoro-phenyl)-2-imidazol-1-yl-1-ethoxy]-5-(pyridin-2-ylsulfonylmethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 63j);

[0281]6-{[1-(1H-Imidazol-1-ylmethyl)pentyl]oxy}-5-[(phenylsulfonyl)methyl]3,4-dihydro-1(2H)-naphthalenone(Compound 63m);

[0282] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-pyrrolylphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 75);

[0283]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(indol-4-yloxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 76);

[0284] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(6-methyl(3-pyridyloxy))methyl]-2,3,4-trihydronaphthalen-1-one (Compound 82);

[0285] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(6-methyl(3-pyridyloxy))methyl]-2,3,4-trihydronaphthalen-1-one (Compound 83);

[0286]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(8-quinolyloxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 94);

[0287] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[4-(trifluoromethoxy)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one (Compound 96);

[0288]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[4-(phenoxy)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one(Compound 97);

[0289]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(6-quinolyloxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 107);

[0290] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-hydroxyethylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 115);

[0291] 6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-phenylethylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 116);

[0292] Methyl3-{[2-((1S)-2-Imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphenyl]methylthio}propanoate(Compound 11-8);

[0293]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(imidazol-2-ylthiomethyl)-2,3,4-trihydronaphthalen-1-one(Compound 119);

[0294]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(1H-1,2,4-triazol-3-ylthiomethyl)-2,3,4-trihydronaphthalen-1-one(Compound 120);

[0295]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(1-methylimidazol-2-ylthio)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 121);

[0296]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(benzothiazol-2-ylthiomethyl)-2,3,4-trihydronaphthalen-1-one(Compound 122);

[0297]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(5-chlorobenzothiazol-2-ylthio)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 123);

[0298]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-furylthiomethyl)-2,3,4-trihydronaphthalen-1-one(Compound 124);

[0299]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(5-nitrobenzimidazol-2-ylthio)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 125);

[0300]2-{[2-((1S)-2-Imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphenyl]methylthio}pyridine-3-carboxylicacid (Compound 126);

[0301]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(1-methyl(1,2,3,4-tetraazol-5-ylthio))methyl]-2,3,4-trihydronaphthalen-1-one(Compound 127);

[0302]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2,2,2-trifluoroethylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 128);

[0303]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-naphenylthiomethyl)-2,3,4-trihydronaphthalen-1-one(Compound 129);

[0304]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-methyl(1,2,4-triazol-3-ylthio))methyl]-2,3,4-trihydronaphthalen-1-one(Compound 136);

[0305]6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-quinolylthiomethyl)-2,3,4-trihydronaphthalen-1-one(Compound 140);

[0306]6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(4-methoxy-benzenesulfinylmethyl)-3,4-dihydro-2H-napthalen-1-one(Compound 141);

[0307]6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(pyridine-2-sulfinylmethyl)-3,4-dihydro-2H-napthalen-1-one(Compound 142);

[0308]6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(propane-2-sulfinylmethyl)-3,4-dihydro-2H-napthalen-1-one(Compound 143);

[0309]N-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-N-β-tolyl-acetamide(Compound 144);

[0310]6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-[1H-indazol-5-ylamino)-methyl]-3,4-dihydro-2H-napthalen-1-one(Compound 145);

[0311]6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(4-phenyl-piperazin-1-ylmethyl)-3,4-dihydro-2H-napthalen-1-one(Compound 146);

[0312]6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(4-pyridin-2-yl-piperazin-1-ylmethyl)-3,4-dihydro-2H-napthalen-1-one(Compound 147);

[0313]6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(quinolin-8-ylaminomethyl)-3,4-dihydro-2H-napthalen-1-one(Compound 148);

[0314]5-(3,4-Dichloro-benzylsulfanylmethyl)-6-((1S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one(Compound 153);

[0315] Methyl2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoate(Compound 154);

[0316] Methyl4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoate(Compound 155);

[0317] Methyl4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoate(Compound 156);

[0318]2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicAcid (Compound 159);

[0319]4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicAcid (Compound 160);

[0320]3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicAcid (Compound 161);

[0321]2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl)-N-methylbenzamide(Compound 164);

[0322]N-(2-Hydroxyethyl)-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 165);

[0323]N-4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoyl-β-alanine(Compound 166);

[0324]N-2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoyl-β-alanine(Compound 167);

[0325]N-3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoyl-β-alanine(Compound 168)

[0326]N-2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoyl-β-alanine(Compound 169);

[0327]N-4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoyl-β-alanine(Compound 170);

[0328]N-3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoyl-β-alanine(Compound 171);

[0329]N-(2-Hydroxyethyl)-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 172);

[0330]N-(2-Hydroxyethyl)-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 173);

[0331]N-(2-Hydroxyethyl)-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 174);

[0332]N-(2-Hydroxyethyl)-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 175);

[0333]N-(2-Hydroxyethyl)-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 176);

[0334]N-[2-(Dimethylamino)ethyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 177);

[0335]N-[2-(Dimethylamino)ethyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 178);

[0336]N-[2-(Dimethylamino)ethyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 179);

[0337]N-[2-(Dimethylamino)ethyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 180);

[0338]N-[2-(Dimethylamino)ethyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 181);

[0339]N-[2-(Dimethylamino)ethyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 182);

[0340] Ethyl3-[(2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoyl)amino]propanoate(Compound 183);

[0341] Ethyl4-[(2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoyl)amino]propanoate (Compound 184);

[0342] Ethyl2-[(2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoyl)amino]propanoate(Compound 185);

[0343] Ethyl2-[(2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoyl)amino]propanoate(Compound 186);

[0344] Ethyl3-[(2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoyl)amino]propanoate(Compound 187);

[0345] Ethyl4-[(2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoyl)amino]propanoate(Compound 188);

[0346]4-{[(2-{[(1S)-2-(1H-2-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-methylbenzamide(Compound 189);

[0347]3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-methylbenzamide(Compound 190);

[0348]4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-methylbenzamide(Compound 191);

[0349]3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-methylbenzamide(Compound 192);

[0350]2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-methylbenzamide(Compound 193);

[0351]N-[(2R)-2-Hydroxypropyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 194);

[0352]N-[(2R)-2-Hydroxypropyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 195);

[0353]N-[(2S)-2-Hydroxypropyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 196);

[0354]N-[(2S)-2-Hydroxypropyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 197);

[0355]N-[(2S)-2-Hydroxypropyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 198);

[0356]N-[(2S)-2-Hydroxypropyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 199);

[0357]N-[(2S)-2-Hydroxypropyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 200);

[0358]N-[(2S)-2-Hydroxypropyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 201);

[0359]N-[(2R)-2-Hydroxypropyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 202);

[0360]N-[(2R)-2-Hydroxypropyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 203);

[0361]N-[(2R)-2-Hydroxypropyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 204);

[0362]N-Allyl-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 205);

[0363]N-Allyl-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 206);

[0364]N-Allyl-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 207);

[0365]N-Allyl-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 208);

[0366]N-Allyl-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 209);

[0367]N-Allyl-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 210);

[0368]2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-(2-propynyl)benzamide(Compound 211);

[0369]4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-(2-propynyl)benzamide(Compound 212);

[0370]3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-(2-propynyl)benzamide(Compound 213);

[0371]4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-(2-propynyl)benzamide(Compound 214);

[0372]3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-(2-propynyl)benzamide(Compound 215);

[0373]2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-(2-propynyl)benzamide(Compound 216);

[0374]N-Cyclopentyl-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 217);

[0375]N-Cyclopentyl-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 218);

[0376]N-Cyclopentyl-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 219);

[0377]N-Cyclopentyl-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 220);

[0378]N-Cyclopentyl-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 221);

[0379]N-Cyclopentyl-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 222);

[0380]N-Cyclopropyl-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 223);

[0381]N-Cyclopropyl-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 224);

[0382]N-Cyclopropyl-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 225);

[0383]N-Cyclopropyl-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 226);

[0384]N-Cyclopropyl-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 227);

[0385]N-Cyclopropyl-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 228);

[0386]N-(2-Furylmethyl)-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 229);

[0387]N-(2-Furylmethyl)-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 230);

[0388]N-(2-Furylmethyl)-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 231);

[0389]N-[2-Hydroxy-1-(hydroxymethyl)ethyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 232);

[0390]N-[2-Hydroxy-1-(hydroxymethyl)ethyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 233);

[0391]N-[2-Hydroxy-1-(hydroxymethyl)ethyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 234);

[0392]N-[2-Hydroxy-1-(hydroxymethyl)ethyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 235);

[0393]N-[2-Hydroxy-1-(hydroxymethyl)ethyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 236);

[0394]N-[2-Hydroxy-1-(hydroxymethyl)ethyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 237);

[0395]N-(2-Furylmethyl)-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 238);

[0396]N-(2-Furylmethyl)-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 239);

[0397]N-(2-Furylmethyl)-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 240);

[0398]N-[(1R)-1-(Hydroxymethyl)propyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 241);

[0399]N-[(1R)-1-(Hydroxymethyl)propyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 242);

[0400]N-[(1R)-1-(Hydroxymethyl)propyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 243);

[0401]N-[(1R)-1-(Hydroxymethyl)propyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 244);

[0402]N-[(1R)-1-(Hydroxymethyl)propyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 245);

[0403]N-[(1R)-1-(Hydroxymethyl)propyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 246);

[0404]4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-[(2S)-2-methylbutyl]benzamide(Compound 247);

[0405]3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-[(2S)-2-methylbutyl]benzamide(Compound 248);

[0406]2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-[(2S)-2-methylbutyl]benzamide(Compound 249);

[0407]2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-[(2S)-2-methylbutyl]benzamide(Compound 250);

[0408]4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-[(2S)-2-methylbutyl]benzamide(Compound 251);

[0409]3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-[(2S)-2-methylbutyl]benzamide(Compound 252);

[0410]N-(2-Hydroxypropyl)-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 253);

[0411]N-(2-Hydroxypropyl)-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 254);

[0412]N-(2-Hydroxypropyl)-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide(Compound 255);

[0413]N-(2-Hydroxypropyl)-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 256);

[0414]N-(2-Hydroxypropyl)-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 257);

[0415]N-(2-Hydroxypropyl)-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide(Compound 258);

[0416]3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-(2-methoxyethyl)benzamide(Compound 259);

[0417]2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-(2-methoxyethyl)benzamide(Compound 260);

[0418]4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-(2-methoxyethyl)benzamide(Compound 261);

[0419]4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-(2-methoxyethyl)benzamide(Compound 262);

[0420]3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-(2-methoxyethyl)benzamide(Compound 263); and

[0421]2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-(2-methoxyethyl)benzamide(Compound 264).

[0422] Illustrative of compounds encompassed by Formula IV include thefollowing list of compounds. This list is meant to be representativeonly and is not intended to limit the scope of the invention in any way:

[0423](±)-6-(2-Imidazolyl-1-(2-pyridyl)ethoxy)-5-(2-phenylethyl)-2,3,4-trihydronaphthalen-1-one(Compound 57);

[0424](±)-6-(2-Imidazolyl-1-(3-pyridyl)ethoxy)-5-(2-phenylethyl)-2,3,4-trihydronaphthalen-1-one(Compound 58);

[0425]6-((S)-2-Imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-phenethyl-3,4-dihydro-2H-naphthalen-1-one(Compound 63a);

[0426]6-((S)-2-Imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-(propane-2-sulfonylmethyl)-3,4-dihydro-2H-napthalen-1-one(Compound 63b);

[0427]6-((S)-2-Imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-(pyridin-2-ylsulfonylmethyl)-3,4-dihydro-2H-napthalen-1-one(Compound 63ba);

[0428]6-((S)-2-Imidazol-1-yl-1-pyridin-3-ethoxy)-5-(2-pyridin-2-yl-ethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 63c);

[0429] Isoquinoline-1-carboxylic acid[2-((S)-2-imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide(Compound 63d);

[0430] Pyrazine-2-carboxylic acid[2-((S)-2-imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide(Compound 63e); and

[0431] Cinnoline-4-carboxylic acid[2-((S)-2-imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide(Compound 63f).

[0432] Additional representative compounds of the present inventioninclude the following list of compounds. This list is meant to berepresentative only and is not intended to limit the scope of theinvention in any way:

[0433]6-((1S)-2-Imidazolyl-1-phenylethoxy)-4-(3-chlorophenyl)-2,3,4-trihydronaphthalen-1-one(Compound 47);

[0434](±)-6-(2-Imidazolyl-1-phenylethoxy)-4-phenyl-2,3,4-trihydro-naphthalen-1-one(Compound 48);

[0435](±)-6-[1-(2-Chlorophenyl)-2-imidazolylethoxy]-5-prop-2-enyl-2,3,4-trihydronaphthalen-1-one(Compound 59);

[0436](±)-6-[1-(2,6-Dichlorophenyl)-2-imidazolylethoxy]-5-prop-2-enyl-2,3,4-trihydronaphthalen-1-one,trifluoroacetic acid (Compound 60);

[0437](±)-6-(2-imidazolyl-1-(2-thienyl)ethoxy)-5-prop-2-enyl-2,3,4-trihydronaphthalen-1-one(Compound 61);

[0438]6-[1-(1H-Imidazol-1-ylmethyl)-2-methylpropoxy]-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone(Compound 63l);

[0439]6-[1-(1H-Imidazol-1-ylmethyl)propoxy]-5-[(phenylsulfonyl)methyl]-3,4-dihydro-[(2H)-naphthalenone(Compound 63n);

[0440](±)-6-[2-(2-Methyl-imidazol-1-yl)-1-phenyl-ethoxy]-5-phenethyl-3,4-dihydro-2H-naphthalen-1-one(Compound 63o);

[0441]6-(2-Imidazol-1-yl-1-thiophen-2-yl-ethoxy)-5-(pyridine-2-sulfonylmethyl)-3,4-dihidro-2H-naphthalen-1-one(Compound 63p);

[0442]6-(2-Imidazol-1-yl-1-thiazol-2-yl-ethoxy)-5-(pyridine-2-sulfonylmethyl)-3,4-dihidro-2H-naphthalen-1-one(Compound 63q); and

[0443]6-[2-(2-Amino-imidazol-1-yl)-1-phenyl-ethoxy]-5-phenethyl-3,4-dihydro-2H-naphthalen-1-one(Compound 63r).

[0444] The compounds of the present invention can be administered to apatient alone or as part of a composition that contains other componentssuch as excipients, diluents, and carriers, all of which are well-knownin the art. The compositions can be administered to humans and animalseither orally, rectally, parenterally (intravenously, intramuscularly,or subcutaneously), intracistemally, intravaginally, intraperitoneally,intravesically, locally (powders, ointments, or drops), or as a buccalor nasal spray. The present invention includes a pharmaceuticalcomposition comprising a compound of Formulas I-VIII and apharmaceutically acceptable excipients, diluents, and carriers thereof.

[0445] Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil), and injectable organic esters suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions and by the use of surfactants.

[0446] These compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

[0447] Solid dosage forms for oral administration include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound is admixed with at least one inert customary excipient(or carrier) such as sodium citrate or dicalcium phosphate or (a)fillers or extenders, as for example, starches, lactose, sucrose,glucose, mannitol, and silicic acid; (b) binders, as for example,carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone,sucrose, and acacia; (c) humectants, as for example, glycerol; (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain complex silicates, andsodium carbonate; (e) solution retarders, as for example paraffin; (f)absorption accelerators, as for example, quaternary ammonium compounds;(g) wetting agents, as for example, cetyl alcohol and glycerolmonostearate; (h) adsorbents, as for example, kaolin and bentonite; and(i) lubricants, as for example, talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, or mixturesthereof. In the case of capsules, tablets, and pills, the dosage formsmay also comprise buffering agents.

[0448] Solid compositions of a similar type may also be employed asfillers in soft and hard-filled gelatin capsules using such excipientsas lactose or milk sugar as well as high molecular weightpolyethyleneglycols, and the like.

[0449] Solid dosage forms such as tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells, such as entericcoatings and others well-known in the art. They may contain opacifyingagents, and can also be of such composition that they release the activecompound or compounds in a certain part of the intestinal tract in adelayed manner. Examples of embedding compositions which can be used arepolymeric substances and waxes. The active compounds can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-mentioned excipients.

[0450] Liquid dosage forms for oral administration includepharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs. In addition to the active compounds, the liquid dosageforms may contain inert diluents commonly used in the art, such as wateror other solvents, solubilizing agents and emulsifiers, as for example,ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide, oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan or mixtures of these substances, cremophor and the like.

[0451] Besides such inert diluents, the composition can also includeadjuvants, such as wetting agents, emulsifying and suspending agents,sweetening, flavoring, and perfuming agents.

[0452] Suspensions, in addition to the active compounds, may containsuspending agents, as for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,or mixtures of these substances, and the like.

[0453] Compositions for rectal administrations are preferablysuppositories which can be prepared by mixing the compounds of thepresent invention with suitable non-irritating excipients or carrierssuch as cocoa butter, polyethyleneglycol, or a suppository wax, whichare solid at ordinary temperatures but liquid at body temperature andtherefore, melt in the rectum or vaginal cavity and release the activecomponent.

[0454] Dosage forms for topical administration of a compound of thisinvention include ointments, powders, sprays, and inhalants. The activecomponent is admixed under sterile conditions with a physiologicallyacceptable carrier and any preservatives, buffers, or propellants as maybe required. Ophthalmic formulations, eye ointments, powders, andsolutions are also contemplated as being within the scope of thisinvention.

[0455] The compounds of the present invention can be administered to apatient at dosage levels in the range of about 0.1 to about 2,000 mg perday. For a normal human adult having a body weight of about 70kilograms, a dosage in the range of about 0.01 to about 100 mg perkilogram of body weight per day is preferable. The specific dosage used,however, can vary. For example, the dosage can depended on a numbers offactors including the requirements of the patient, the severity of thecondition being treated, and the pharmacological activity of thecompound being used. The determination of optimum dosages for aparticular patient is well known to those skilled in the art.

[0456] The compounds of the present invention can exist in differentstereoisomeric forms by virtue of the presence of asymmetric centers inthe compounds. It is contemplated that all stereoisomeric forms of thecompounds as well as mixtures thereof, including racemic mixtures, formpart of this invention.

[0457] In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

[0458] The examples presented below are intended to illustrateparticular embodiments of the invention, and are not intended to limitthe scope of the specification or the claims in any way.

[0459] An illustration of the preparation of compounds of the presentinvention is shown below in Schemes 1 to 23. Q through Q¹³ are definedbelow. L is an appropriate leaving group, such as a halide orequivalent. W, R³, R^(3a), X, R⁵, Y, R⁶, and R^(6a) refer to thesubstituents in Formula I. R⁷ refers to the substituents in Formula II.R⁹, R¹⁰, R¹¹, R¹³, R¹⁴ refer to the substituents in Formula III. R¹⁵refers to the substituents in Formula IV. X′ and Y′ refer to thesubstituents in Formula V. R″ represents any of the substituents listedfor “substituted aryl” above.

[0460] Armed with the disclosure provided herein (particularly theschemes and the synthetic examples that follow) and knowledge common toall who practice in the field, those of ordinary skill in the art willbe able to make and use the entire scope of compounds disclosed herein.

[0461] The compounds of Formulas I-V are synthesized according to theabove Schemes.

[0462] Accordingly, Scheme 1 depicts the synthesis of those compounds ofFormula I wherein W=CH₂CH₂, R³=phenyl, R^(3a)=hydrogen, R⁵=hydrogen,X=CH₂SR⁶, R⁶ is hydrogen, C₁-C₆-alkyl, phenyl, benzyl or substitutedphenyl, and Y=O. Scheme 1 also depicts the synthesis of those compoundsof Formula II wherein R⁷ is —S—(C₁-C₆)alkyl, —S-phenyl, or—S-substituted phenyl. Finally, Scheme 1 depicts the synthesis of thosecompounds of Formula III wherein R⁹=phenyl, R¹⁰=hydrogen or —CH₂OH andR¹¹ is —SO-aryl, —SO₂-aryl, —SO₂-alkyl, —S(O)z-heteroaryl, —S-aryl,—S(O)z-substituted alkyl, and —S(O)z-substituted arylalkyl.

[0463] Chloromethyltetralone (Chem. Pharm. Bull. 1977;25(11):2988) istreated with a thiol or thiophenol in the presence of a base in asolvent such as THF to yield a thioether. Oxidation with an oxidant suchas mCPBA in a solvent such as dichloromethane affords the sulfone.Mitsunobu reaction of the sulfone with the imidazole alcohol in thepresence of triphenylphosphine/diethyl azodicarboxylate (DEAD) in asolvent such as THF affords the6-((1S)-2-imidazolyl-1-phenylethoxy)-sulfone. Treatment of the sulfoxidewith paraformaldehyde in a solvent such as DMSO affords the methylenealcohol substituted imidazole. Similarly, Mitsunobu reaction of thethioether with the imidazole alcohol in the presence oftriphenylphosphine/DEAD in a solvent such as THF affords the thioether.Oxidation of the thioether with an oxidant such as sodium periodate in asolvent such as THF yields the corresponding sulfoxide.

[0464] Compounds such as those of Formula I wherein W=CH₂CH₂, R³=phenyl,X=CH₂NR⁶R^(6a) and Y=O can be synthesized as set forth in Scheme 2.Scheme 2 also depicts the synthesis of those compounds of Formula IIwherein R⁷ is —NH-phenyl or —NH-substituted phenyl.5-chloromethyltetralone is treated with an amine in a solvent such asTHF to afford the aminomethyl tetralone. Mitsunobu reaction of theaminomethyl tetralone with the imidazole alcohol in the presence oftriphenylphosphine/DEAD in a solvent such as THF affords the6-((1S)-2-imidazolyl-1-phenylethoxy)-5-substituted aminomethyltetralone.

[0465] Compounds such as those of Formula I wherein W=CH₂CH₂, R³=phenyl,X=CH₂OR⁶, R⁶ cannot be hydrogen, and Y=O can also be synthesized as setforth in Scheme 2. Scheme 2 also depicts the synthesis of thosecompounds of Formula II wherein R⁷ is alkoxy, —O—(C₃-C₆)cycloalkyl,—O—(C₂-C₆)alkenyl, —O-phenyl, —O-substituted phenyl, or —O-benzyl.Additionally, Scheme 2 depicts the synthesis of those compounds ofFormula III wherein R⁹=phenyl and R¹¹=—O-substituted alkyl.5-Chloromethyltetralone is treated with an alcohol in a solvent such asTHF in the presence of a base to afford the ether. Mitsunobu reaction ofthe ether with the imidazole alcohol in the presence oftriphenylphosphine/DEAD in a solvent such as THF affords the6-((1S)-2-imidazolyl-1-phenylethoxy)-ether.

[0466] Scheme 3 depicts the synthesis of6-((1S)-2-imidazolyl-1-phenylethoxy)-5-substituted alkyl tetralones.Compounds such as those of Formula I wherein W=CH₂CH₂, R³=phenyl, Y=Oand X is arylalkyl, substituted arylalkyl, heteroarylalkyl or—CH₂CH₂CO₂R⁶ can be synthesized as set forth in Scheme 3. Q₁ includesaryl, heteroaryl, substituted aryl and CO₂R⁶. 5-Bromotetralone (Z. Chem.1970; 10:70) is treated with an acetylene in the presence of a palladiumcatalyst such as Pd(PPh₃)₂Cl₂ and copper iodide in a solvent such asDMF/Et₃N to afford the 5-substituted acetylene tetralone. Alternatively,the 5-bromotetralone is treated with an alkene in the presence of apalladium catalyst such as Pd(PhCN)₂Cl₂, sodium acetate andN,N-dimethylglycine and heated in a solvent such as methanol to affordthe 5-substituted alkenyl tetralone. Reduction of either the5-substituted acetylene tetralone or the 5-substituted alkenyl tetralonewith a catalyst such as Pd/BaSO₄ in the presence of H₂ in a solvent suchas THF yields the 5-substituted alkyl tetralone. Removal of the methoxyprotecting group with potassium cyanide in a solvent such as DMSO yieldsthe corresponding phenol. Mitsunobu reaction of the ether with theimidazole alcohol in the presence of triphenylphosphine/DEAD in asolvent such as THF affords the6-((1S)-2-imidazolyl-1-phenylethoxy)-5-substituted alkyl tetralone.

[0467] Scheme 3 also shows the synthesis of generally6-((1S)-2-imidazolyl-1-phenylethoxy)-5-X substituted tetralones.Compounds such as those of Formula I wherein W=CH₂CH₂, R³=phenyl, Y=Oand X is aryl or substituted aryl can be synthesized as set forth inScheme 3. 5-Bromotetralone is treated with a boronic acid derivative inthe presence of a palladium catalyst such as Pd(PPh₃)₄ in a solvent suchas DME to afford tetralone derivative. Removal of the methoxy protectinggroup with sodium cyanide in a solvent such as DMSO yields the phenol.Mitsunobu reaction of the ether with the imidazole alcohol in thepresence of triphenylphosphine/DEAD in a solvent such as TIF affords the6-((1S)-2-imidazolyl-1-phenylethoxy)-5-X substituted tetralone. When thesidechain of the 5-substituted alkyl tetralone contains a nitrogenheterocycle such as pyridyl, or isoquinoline it can be oxidized to theN-oxide with mCPBA in a solvent such as dichloromethane.

[0468] Compounds such as those of Formula I wherein W=CH₂CH₂, R³=phenyl,Y=O and X is substituted arylalkyl can be synthesized as set forth inScheme 4. Q² includes substituted aryl. In Scheme 4, 5-bromotetralone istreated with a zinc reagent in the presence of a palladium catalyst suchas palladium bis(dibenzylideneacetone) or bis diphenylphosphino)ferrocene in a solvent such as THF in an inert atmosphere to afford atetralone derivative. Removal of the methoxy protecting group withsodium cyanide in a solvent such as DMSO yields the phenol. Mitsunobureaction of the ether with the imidazole alcohol in the presence oftriphenylphosphine/DEAD in a solvent such as THF affords the6-[(1S)-2-imidazolyl-1-phenylethoxy]-5-substituted methyl tetralone.

[0469] Compounds such as those of Formula I wherein W=CH₂CH₂, R³=phenyl,Y=O and X is halogen or heteroaryl can be synthesized as set forth inScheme 4. Also in Scheme 4, 5-bromotetralone is converted to a phenol bytreatment with boron tribromide. The Mitsunobu reaction then affords the5-bromo-tetralone. The 5-bromo-tetralone is coupled with a boronic acidderivative in the presence of a palladium catalyst such as Pd(PPh₃)₄ ina solvent such as DME to afford a 5-X substituted tetralone.

[0470] The compounds of Formula I wherein X=amino are synthesized as setforth in Scheme 5. Scheme 5 depicts the synthesis of those compounds ofFormula III wherein R⁹=phenyl and R¹¹=—NHSO₂—R¹⁴, —NHCO—R¹⁴,NHCO-heteroaryl-O-aryl, or NHCO-heteroaryl-substituted aryl. Q³ includesthe definition of R^(6′) for Formula V. 5-Nitro-tetralone is convertedto the 6-[(1S)-2-imidazolyl-1-phenylethoxy]-5-nitro tetralone via theMitsunobu reaction. This compound is reduced to the aniline in thepresence of iron/acetic acid in a solvent such as methanol/water. Theaniline is treated with sulfonyl chloride in the presence of a base suchas pyridine in a solvent such as dichloromethane to afford the5-sulfonamide-tetralone. Alternatively, the aniline is treated with acarboxylic acid in the presence of a coupling agent such as EDCI or CDIin a solvent such as DMF to afford a 5-amido-tetralone. Finally, theaniline is also treated with an alkylhalide or equivalent in thepresence of a base such as Et₃N to afford the 5-amino-tetralone.

[0471] Scheme 6 depicts the synthesis of compounds such as those ofFormula III wherein R⁹=phenyl and R¹¹ is —NHCO₂-alkyl, —NHSO₂—R¹⁴,—NHCO—R¹⁴, NHCOC(substituted alkyl)NHCO₂-alkyl, or —NHCO—C(substitutedalkyl)amino. 6-Hydroxytetralone is aminoalkylated with hydroxymethylderivative in the presence of H₂SO₄ in acetic acid to afford theaminoalkylated tetralone. The Bis Boc protected tetralone is obtainedvia treatment of the aminoalkylated tetralone with Boc anhydride in thepresence of DMAP in THF. Hydrolysis of the Bis Boc protected tetralonewith LiOH in THF/MeOH/H₂O affords a mixture of mono and bis N-Bocderivatives. Treatment of this latter mixture with Mg(ClO₄)₂ inacetonitrile affords the mono Boc product. The subsequent Mitsunobureaction affords the Boc protected amine which is deprotected underacidic conditions such as HCl in a solvent such as dioxane to afford the5-aminomethyl-tetralone. This compound is then treated with sulfonylchloride in the presence of a base such as pyridine in a solvent such asdichloromethane to afford the 5-sulfonamidomethyl-tetralone.Alternatively, the 5-aminomethyl-tetralone is treated with a carboxylicacid in the presence of a coupling agent such as EDCI or CDI in asolvent such as DMF to afford the 5-amidomethyl-tetralone.

[0472] The synthesis of Compound 43 is depicted in Scheme 7.6-Hydroxytetralone is aminoalkylated with hydroxymethyl phthalimide inthe presence of H₂SO₄ to afford the 5-phthalimido methyl tetralone.Subsequent Mitsunobu reaction affords2-{[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphenyl]methyl}isoindoline-1,3-dione(Compound 43).

[0473] The compounds disclosed in Formula V wherein X′=(CH₂)_(n)R^(1′)R^(1′a) and Y′=O are synthesized as set forth in Scheme8. Compounds such as those of Formula I wherein W=CH₂CH₂, R³=phenyl, Y=Oand X is arylalkyl can be synthesized as set forth in Scheme 8.(CH₂)_(n)R¹R^(1a) is defined as shown above for (CH₂)_(n)R^(1′)R^(1′a)in Formula V. (CH₂)_(n)R¹R^(1a) can also be defined as arylalkyl. Theoxazoline (J. Org. Chem. 1978;43:1372) is treated with a Grignardreagent prepared by methods known by those skilled in the art, in asolvent such as THF to afford the 5-(CH₂)_(n)R¹R^(1a) oxazoline. Removalof the oxazoline under acidic conditions such as 18% HCl affords thecorresponding carboxylic acid. The carboxylic acid can be 3-carbonhomologated by methods known to those skilled in the art to afford thebutyric acid compound via reduction, halogenation, acrylate coupling,another reduction, and finally hydrolysis. Intramolecular Friedel-Craftsacylation of the butyric acid by treatment with trifluoroacetic acidanhydride in dichloromethane gives the tetralone. Removal of the methoxyprotecting group of with sodium cyanide in a solvent such as DMSO yieldsthe phenol. Mitsunobu reaction of the phenol affords the5-(CH₂)_(n)R¹R^(1a) tetralone.

[0474] The compounds disclosed in Formula V wherein X′=(CH₂)_(n)R^(1′)R^(1′a) and Y′=O are synthesized as set forth in Scheme9. Compounds such as those of Formula I wherein W=CH₂CH₂, R³=phenyl, Y=Oand X is arylalkyl or heteroarylalkyl can be synthesized as set forth inScheme 9. (CH₂)_(n)R¹R^(1a) is defined as shown above for(CH₂)_(n)R^(1′)R^(1′a) in Formula V. (CH₂)_(n)R¹R^(1a) can also bedefined as arylalkyl or heteroarylalkyl. The oxazoline as shown inscheme 9 (J. Org. Chem. 1978;43:1372) is treated with a Grignard reagentprepared by methods known by those skilled in the art, in a solvent suchas THF to afford the 5-(CH₂)_(n)R¹R^(1a) oxazoline. Removal of theoxazoline under acidic conditions such as 18% HCl affords thecorresponding carboxylic acid. The carboxylic acid can be 3-carbonhomologated by methods known to those skilled in the art to afford thebutyric acid compound via reduction, halogenation, malonatedisplacement, hydrolysis, another reduction, halogenation, displacementwith cyanide and finally hydrolysis. Intramolecular Friedel-Craftsacylation of the bytyric acid by treatment with trifluoroacetic acidanhydride in dichloromethane gives the tetralone. Removal of the methoxyprotecting group of with sodium cyanide in a solvent such as DMSO yieldsthe phenol. Mitsunobu reaction of the phenol affords the5-(CH₂)_(n)R¹R^(1a) tetralone.

[0475] The compounds of Formula I wherein W=CH₂CH₂, R³=phenyl, Y=O and Xis arylalkyl or substituted arylalkyl can be synthesized as set forth inScheme 10. Scheme 10 also depicts the synthesis of Compound 45. Q⁴includes aryl, arylalkyl, substituted aryl, and substituted arylalkyl.Condensation of 3-methoxybenzoyl chloride with2-amino-2-methyl-1-propanol in dichloromethane affords the correspondingamide. Cyclization of the amide to the oxazolidine is achieved withthionyl chloride. Acylation of the oxazolidine with an acid chloride inthe presence of a base such as butyl lithium and in a solvent such asTHF affords a 2-substituted carboxy phenyl. Deprotection under acidicconditions such as 18% HCl affords the carboxylic acid. Reduction of thebenzylic ketone is achieved in the presence of a catalyst such as 5%Pd/C in the presence of H₂ and in a solvent such as MeOH to afford the2-CH₂R″-3-methoxy benzoic acid. This compound is 3-carbon homologated tothe butyric acid using the 5-step method described above for Scheme 8.Intramolecular Friedel-Crafts acylation of the resulting3-(2-CH₂Q⁴-3-methoxyphenyl) butyric acid is achieved by treatment withpolyphosphate ester in chloroform to give the tetralone. Removal of themethoxy protecting group with sodium cyanide in a solvent such as DMSOyields the phenol. The subsequent Mitsunobu reaction affords the 5-CH₂Q⁴tetralone.

[0476] Scheme 11 outlines the synthesis of Compound 46, which is acompound of Formula III. 2,3-Dimethoxybenzyl alcohol is 3-carbonhomologated to the butyric acid using the 4-step method described abovein Scheme 8 (i.e. from benzyl alcohol to butyric acid). IntramolecularFriedel-Crafts acylation of the acid by treatment with polyphosphateester in chloroform gives the tetralone. Selective removal of the5-methoxy protecting group with methane sulfonic acid/methionine affordsthe phenol. O-Phenylation of the phenol is carried out withtriphenylbismuth in the presence of Cu(OAc)₂, a base such as Et₃N and asolvent such as THF. Removal of the methoxy protecting group with sodiumcyanide in a solvent such as DMSO yields6-hydroxy-5-phenoxy-2,3,4-trihydronaphthalen-1-one. The standardMitsunobu reaction then affords6-((1S)-2-imidazolyl-1-phenylethoxy)-5-phenoxy-2,3,4-trihydronaphthalen-1-one(Compound 46).

[0477] Compounds such as Compound 47 and Compound 48 are synthesized asset forth in Scheme 12. Q⁵ represents any of the substituents listed for“substituted aryl” above. 7-Methoxytetralone is treated with a Grignardreagent, obtained by those skilled in the art from, for example, anarylbromide and magnesium, to yield the alcohol. Elimination withcatalytic tosic acid in benzene and reduction with 10% Pd/C affords the7-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalene. Subsequent oxidationwith an oxidant such as CrO₃ in a solvent such as acetic acid affordsthe corresponding tetralone. Removal of the methoxy protecting groupwith sodium cyanide in a solvent such as DMSO yields the phenol, whichis then converted to the6-((1S)-2-imidazolyl-1-phenylethoxy)-4-phenyl-2,3,4-trihydronaphthalen-1-onevia the Mitsunobu reaction.

[0478] The synthesis of compounds described in Scheme 12 arealternatively prepared by the route depicted in Scheme 13. Abenzophenone is condensed with methylbromoacetate in the presence ofzinc and catalytic iodine to afford amethyl-3-(3-methoxyphenyl)-3-phenylprop-2-enoate. Catalytic reductionwith Pd/C in the presence of H₂ in a solvent such as MeOH yields theester. One carbon homologation of the ester to the butyric acid isachieved by methods known in the art, via reduction, bromination,conversion to nitrile, and hydrolysis. Intramolecular Friedel-Craftsacylation of the acid gives the tetralone of Scheme 12. Conversion ofthe tetralone to the6-((1S)-2-imidazolyl-1-phenylethoxy)-4-phenyl-2,3,4-trihydronaphthalen-1-oneis as described above.

[0479] Preparation of 2-imidazolyl-1-R3-ethoxy prop-2-enyl tetralone andindanone derivatives of Formula I and Formula V are depicted in Scheme14. The compounds of Formula I wherein Y=O and X is lower alkyl or loweralkenyl can be synthesized as set forth in Scheme 14. Q⁶ represents anyof the substituents listed for “substituted aryl” above. Initially,imidazole is reacted with a chiral epoxide, either obtained commerciallyor synthesized (Science, 1977;277:936), in the presence of a base suchas pyridine in a solvent such as EtOH, DMF or DMSO to yield the desiredimidazole alcohol.

[0480] A commercially available hydroxy-tetralone or hydroxyindanone istreated with an allyl bromide in the presence of a base such as Cs₂CO₃in a solvent such as DMF to afford the ether. Claisen rearrangement in asolvent such as diethylaniline affords the substituted tetralone orindanone. The Mitsunobu reaction then affords the2-imidazolyl-1-R³-ethoxy)prop-2-enyl compound. Alternatively, thesubstituted tetralone or indanone is reduced with a catalyst such asRhCl(PPh₃)₃ in the presence of H₂ neat to afford a (prop-2-enyl)phenolderivative. Mitsunobu reaction of the phenol the desired imidazolealcohol affords the 2-imidazolyl-1-R3-ethoxy prop-2-enyl tetralone orindanone derivative.

[0481] The compounds of Formula IV wherein Y=O and X cannot be NH₂ aresynthesized as set forth in Scheme 15. Scheme 15 depicts the synthesisof compounds such as Compound 57 and 58. Glycolic acid ethyl ester isprotected as a tetrahydropyranyl ether via coupling under acidicconditions such as Tosic acid, with dihydropyran in a solvent such asdichloromethane to afford an ester. A heteroaryl halide is treated withan organometalic reagent such as butyl lithium in a solvent such as TBFto afford the heteroaryllithium reagent, which is subsequently treatedwith the ether in situ to afford a ketone. Reduction of the ketone witha reducing agent such as sodium borohydride in a solvent such asmethanol affords the alcohol. Mitsunobu reaction of the alcohol with aphenolic tetralone, synthesized according to several previous Schemes,in the presence of triphenylphosphine/DEAD and in a solvent such as THFaffords the 5,6-substituted-tetralone. Deprotection of the THP etherunder acidic conditions such as acetic acid/THF/H₂O yields the6-[2-(hydroxy)-1-R³-ethoxy]-5-X-2,3,4-trihydronaphthalen-1-one.Treatment of this compound with a mixture of imidazole and a base suchas sodium hydride in the presence of trifluoromethanesulfonic acidanhydride in a solvent such as THF affords a6-(2-imidazolyl-1-R³-ethoxy)-5-X-2,3,4-trihydronaphthalen-1-one.

[0482] Compounds such as those of Formula I wherein Y=O and X cannot beNH₂ are synthesized as set forth in Scheme 16. Compounds such asCompound 58a are synthesized as depicted in Scheme 16.6-Hydroxy-5-(2-phenylethyl)-3,4-dihydro-1(2H)-naphthalenone synthesizedas set forth in Scheme 3 is condensed with 2-bromo-2-methylpropionate inthe presence of a base such as potassium carbonate in a solvent such asacetonitrile to afford an ether. The ester is converted to the diol withlithium aluminum hydride in THF and the secondary alcohol is reoxidizedto the ketone with manganese dioxide in THF. The resulting alcohol isthen converted to the trifluoromethanesulfonate via treatment withtrifluromethanesulfonic anhydride. Displacement of thetrifluoromethanesulfonate with imidazole affords compound 58a.

[0483] The compounds of Scheme 15 are alternatively prepared accordingto the route depicted in Scheme 17. Acetophenone is treated with bromineto afford bromoketone. Reduction of the ketone with a reducing agentsuch as sodium borohydride in a solvent such as methanol affords thebromoalcohol. Imidazole is then reacted with the bromoalcohol in thepresence of a base such as pyridine and in a solvent such as EtOH, DMFor DMSO to yield an imidazole alcohol. Mitsunobu reaction of thisalcohol with a desired phenol affords the corresponding6-(2-imidazolyl-1-R³-ethoxy)-5-X-2,3,4-trihydronaphthalen-1-one.

[0484] Compounds such as those of Formula IV wherein Y=O, X isrepresented by (CH₂)y-R¹⁵, R¹⁵ is —SO₂-alkyl or —SO₂-heteroaryl, and R¹⁴is heteroaryl are synthesized as set forth in Scheme 18. Scheme 18 alsodepicts the compounds of Formula III wherein R⁹ is C₁-C₆ alkyl orsubstituted phenyl, X is represented by (CH₂)y-R¹¹ and R¹¹ is—SO₂-alkyl, —SO₂-aryl, or —S(O)z-heteroaryl, and R¹⁴ is heteroaryl.Finally, Scheme 18 depicts compounds such as those of Formula I whereinR³ is substituted phenyl or R⁵ is C₁-C₆ alkyl. Imidazole or substitutedimidazole is condensed with an epoxide, the synthesis of which is knownto those skilled in the art. The subsequent imidazole alcohol is thensubjected to Mitsunobu reaction as described previously with atetralone, the synthesis of which has been shown in several schemes.When the tetralone where X=NO₂ is used. The product can be reduced withiron powder in acetic acid to give the aniline. The aniline is thenreacted with carboxylic acids to afford the amides of Formula I whereinX=NHCOR⁶ or the compounds of Formula III or IV wherein R¹⁴ isheteroaryl.

[0485] The compounds of Formula I wherein R³=phenyl or substitutedphenyl, Formula III wherein R⁹=phenyl or substituted phenyl, Formula IVwherein Q⁸=heteroaryl, and Formula V wherein Q⁸=phenyl, substitutedphenyl, heteroaryl, or substituted heteroaryl are synthesized as setforth in Scheme 19. For the compounds of Scheme 19, X cannot be NH₂.Scheme 19 also depicts compounds such as Compound 63p and 63q. Imidazoleis reacted with 2-chloro-N-methoxy-N-methylacetamide to afford2-imidazol-1-yl-N-methoxy-N-methyl-acetamide. The acetamide is reactedwith a Grignard reagent prepared from magnesium and aryl or heteroarylhalide to give the corresponding ketone. Reduction of the ketone isaccomplished with NaBH₄ in a solvent such as methanol to afford thealcohol which is subjected to Mitsunobu reaction with a tetralone asdescribed previously.

[0486] Scheme 20 sets forth the synthesis of compounds such as those ofFormula I wherein R⁵ is amino. The anion obtained from reacting 2-nitroimidazole with sodium metal is reacted with an acylbromide known in theart. The subsequent ketone is reduced with sodium borohydride in asolvent such as methanol to give the alcohol which is subjected toMitsunobu reaction with a tetralone as described previously. Theresultant 2-nitroimidazole is reduced to the 2-amino imidazole with ironpowder in acetic acid.

[0487] The compounds of Formula I and Formula V wherein Y=S aresynthesized as set forth in Scheme 21. A desired phenol reacted withN,N-dimethylthiocarbamoyl chloride in the presence of a base such ascesium carbonate in a solvent such as DMF gives a thiocarbamate. Thermalrearrangement of the thiocarbamate is achieved by heating it neat at240° C. to afford the corresponding thiocarboxamide. Hydrolysis of thethiocarboxamide is carried out in the presence of a base such as sodiumhydroxide in a solvent such as methanol to afford a thiophenol. TheMitsunobu reaction of the imidazole alcohol with the thiophenol affordsthe6-((1S)-2-imidazolyl-1-phenyl-ethylsulfanyl)-5-X-2,3,4-trihydronaphthalen-1-one.

[0488] Compounds such as those of Formula I wherein X=—CH₂NR⁶R^(6a) areset forth in Scheme 22. Compounds such as those of Formula III whereinR¹¹=—SO—substituted aryl, —S(O)z-heteroaryl, SO-alkyl, —NH-substitutedaryl, NH-heteroaryl, —NH—(CH₂)₂—O-heteroaryl, or —N(CO-alkyl)substitutedaryl are also depicted in Scheme 22. Finally, the compounds of Formula Vwherein X′=CH₂OR^(6′)—CH₂NR^(6′)R^(6′a), or CH₂S(O)_(z′)R^(6′) and Y′=Ocan be synthesized as set forth in Scheme 22. Q⁹ includes substitutedaryl, heteroaryl, —(CH₂)₂—O-heteroaryl and the definition of R⁶ andR^(6′). Q ¹⁰ includes CO-alkyl and the definition of R^(6a). Q ¹¹includes the definition of R^(6′). Q¹² includes substituted aryl,heteroaryl and alkyl and the definition of R^(6′). Chloromethyltetralone(Chem. Pharm. Bull. 1977;25(11):2988) is treated with methanol indiisopropylamine to yield methoxymethyltetralone. Mitsunobu reaction ofthis tetralone with the imidazole affords6-((1S)-2-imidazolyl-1-phenylethoxy)-5-(methoxymethyl)-2,3,4-trihydronaphthalen-1-one.Conversion to the bromide is achieved via treatment with HBr in aceticacid. The bromide is treated either with an amine, a thiol or an alcoholin a solvent such as THF to yield an amine, a thioether or an ether,respectively. Selective oxidation of the thioether with an oxaziridineaffords the sulfoxides.

[0489] Compounds such as those of Formula I wherein X=CH₂SR⁶ are setforth in Scheme 23. Scheme 23 also depicts compounds such as those ofFormula III wherein R¹¹=—SO₂-substituted aryl, or—S(O)z-phenyl-CONH—R¹³. Q¹³ is generally hydrogen.-5-chloromethyl-6-hydroxy-3,4-dihydro-2H-napthalen-1-one is reacted withmethyl-2,3 or 4-mercaptobenzoate in the presence of a base such astriethylamine in a solvent such as dichloromethane to afford thethioether. The thioether is oxidized with mCPBA in a solvent such asdichloromethane to afford the sulfone. Coupling of the tetralone sulfonewith an alcohol under previously described Mitsunobu conditions affordthe compounds of Formula III wherein R¹¹=—S₂—substituted aryl, whereinthe substituent is CO₂CH₃. Subsequent hydrolysis of the ester underconditions known in the art affords the carboxylic acids which arecoupled with amines under conditions known in the art to give theamides.

[0490] In addition, the compounds of Formula I wherein X=CH₂SR⁶ can besynthesized from the thioether shown in Scheme 23. The coupling of thetetralone thioether with an alcohol under previously described Mitsunobuconditions followed by hydrolysis and amide coupling as describedpreviously affords the thioether amides.

[0491] The disclosures in this application of all articles andreferences, including patents, are incorporated herein by reference.

[0492] The invention is illustrated further by the following exampleswhich are not to be construed as limiting the invention in scope orspirit to the specific procedures described in them.

[0493] The starting materials and various intermediates may be obtainedfrom commercial sources, prepared from commercially available organiccompounds, or prepared using well known synthetic methods.

[0494] Representative examples of methods for preparing intermediates ofthe invention are set forth below.

EXAMPLE 1

[0495] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(phenylthiomethyl)-2,3,4-trihydronaphthalen-1-one(Compound 1)

[0496] 1. 6-Hydroxy-5-phenylthiomethyl-2,3,4-trihydronaphthalen-1-one

[0497] To a solution of thiophenol (9.42 g, 0.0855 mol) in oxygen-freetetrahydrofuran (100 mL) is added diisopropylamine (3.68 g, 0.0285 mol).5-Chloromethyl-6-hydroxy-2,3,4-trihydronaphthalen-1-one, prepared asdescribed in Chem. Pharm. Bull. 1977;25(11):2988-3002 (6.0 g, 0.0285mol) is dissolved in tetrahydrofuran (200 mL) and the solution addeddropwise to the preceding solution at 25° C. The mixture is stirred for2 hours, concentrated in vacuo and the residue layered with ethyl ether.The suspension is extracted with 1N NaOH, which is separated and washedwith ethyl ether. Upon standing a solid precipitate forms within theaqueous phase. The solid is filtered, dissolved in ethyl acetate, andthe solution is washed with 1N citric acid, brine and dried overanhydrous magnesium sulfate. The suspension is filtered and the filtrateis evaporated in vacuo giving a white solid, 4.68 g, 58% yield. MS:APCI: M+1: 285.1 (M: 284.4). NMR spectrum is consistent with structure.

[0498] 2.6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(phenylthiomethyl)-2,3,4-trihydronaphthalen-1-one

[0499] (R)-2-Imidazol-1-yl-1-phenyl-ethanol (1.45 g, 7.73 mmol),triphenylphosphine (2.77 g, 10.5 mmol), and6-hydroxy-5-phenylsulfanylmethyl-2,3,4-trihydronaphthalen-1-one (2.0 g,7.03 mmol) are suspended in dry tetrahydrofuran (100 mL). To thesuspension is added a solution of diethyl azodicarboxylate (1.83 g, 10.5mmol) in tetrahydrofuran (25 mL). After stirring for 3 hours at 25° C.,the mixture is evaporated to a syrup in vacuo. To the residue is addedethyl ether and 1N citric acid which gives a solution that precipitatesa white solid. The solid is filtered and added to a mixture of saturatedsodium bicarbonate solution and ethyl ether. The ether phase of theresulting solution is separated, washed with brine, dried over anhydrousmagnesium sulfate and filtered. The filtrate is evaporated in vacuo to awhite solid (1.0 g, 31% yield). MS: APCI: M+1: 455.1 (M: 454.6). NMRspectrum is consistent with structure (Compound 1). Calcd. forC₂₈H₂₆N₂O₂S.0.20H₂O: Theory: C 73.40, H 5.72, N 6.11, H₂O 0.79. Found: C73.07, H 5.91, N 6.15, H₂O 0.45.

EXAMPLE 2

[0500] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(phenylsulfinyl)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 2)

[0501] To an ice cold solution of compound 1 (0.60 g, 1.32 mmol) in 10mL tetrahydrofuran is added a solution of NaIO₄ (3.3 mL 0.5M in H₂O).The mixture is stirred 3 days at 25° C. Another portion of NaIO₄solution (6.6 mL 0.5M in H₂O) is added and after stirring for 6 hours at25° C., the mixture is filtered and the filtrate is extracted withchloroform. The organic phase is washed with brine, dried over anhydrousmagnesium sulfate, and filtered. The filtrate is evaporated to a solid(550 mg). The mixture is purified by reverse phase silica gelchromatography giving the product (Compound 2) as a trifluoroacetatesalt (100 mg, 16% yield). MS: APCI: M+1: 471.1 (M: 470.6). NMR spectrumis consistent with structure. Calcd. for C₂₈H₂₆N₂O₃S.0.10H₂O.1.45 TFA:Theory: C 58.20, H 4.34, N 4.39, H₂O 0.28 F 12.96. Found: C 58.51, H4.61, N 4.23, H₂O <0.1 F 13.00.

EXAMPLE 3

[0502] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(phenylsulfinyl)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 3)

[0503] 1.5-Benzenesulfonylmethyl-6-hydroxy-2,3,4-dihydronaphthalen-1-one

[0504] To a suspension of6-hydroxy-5-phenylsulfanylmethyl-2,3,4-trihydronaphthalen-1-one (7.0 g,0.025 mol) in 300 mL dichloromethane is added a solution of 73%meta-chloroperbenzoic acid (11.82 g, 0.05 mol) in 150 mLdichloromethane. The suspended solids dissolve, followed byprecipitation of another white solid. After stirring 3 hours at 25° C.,an additional portion of 73% meta-chloroperbenzoic acid (2.95 g, 0.0125mol) in 11 mL dichloromethane is added. The mixture is then stirred for1 hour and extracted with saturated potassium carbonate solution (475mL). The organic phase is washed with brine, dried over anhydrousmagnesium sulfate, filtered, and evaporated to a solid. The pH of thecarbonate is adjusted to 8 with concentrated HCl and washed with ethylacetate. The ethyl acetate is washed with brine, dried over anhydrousmagnesium sulfate, filtered and evaporated to a solid. The solids fromboth organic phases are combined and crystallized from ethyl acetate,filtered, and dried giving a white solid (5.07 g, 64% yield). MS: APCI:M+1: 317 (M: 316.4). NMR spectrum is consistent with structure.

[0505] 2.6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(phenylsulfonyl)methyl]-2,3,4-trihydronaphthalen-1-one

[0506] (R)-2-Imidazol-1-yl-1-phenyl-ethanol (3.27 g, 17.4 mmol),triphenylphosphine (6.22 g, 23.7 mmol), and5-benzenesulfonylmethyl-6-hydroxy-2,3,4-trihydronaphthalen-1-one (5.0 g,15.8 mmol) are suspended in dry tetrahydrofuran (250 mL). To thesuspension is added a solution of diethyl azodicarboxylate (4.13 g, 23.7mmol) in tetrahydrofuran (50 mL) over 45 minutes. After stirring for 23hours at 25° C., the mixture is evaporated to a syrup in vacuo. Theresidue is dissolved in ethyl ether and 1N citric acid. The ether phaseis decanted from the mixture and the citric acid phase is washedexhaustively with ethyl ether. The pH of the citric acid phase isadjusted to 13 with 6N NaOH giving a white solid precipitate. The solidis filtered and dissolved in dichloromethane, which is washed withbrine, dried over anhydrous magnesium sulfate and filtered. The filtrateis evaporated in vacuo to give a foam. The product is purified bychromatography on 200 g silica gel eluted with chloroform/1% methanol.The product (Compound 3) is obtained from chloroform/ethyl ether as acrystalline solid (3.53 g, 46% yield). MS: NMR spectrum is consistentwith structure. Calcd. for C₂₈H₂₆N₂O₄S: Theory: C 69.12, H 5.39, N 5.76.Found: C 68.80, H 5.44, N 5.68.

EXAMPLE 4

[0507] Synthesis of Methyl2-{[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]methylthio}benzoate(Compound 4)

[0508] 1. Methyl2-(2-hydroxy-5-oxo-6,7,8-trihydronaphthalenylmethylthio) benzoate

[0509] To a solution of methyl thiosalicylate (14.38 g, 85.5 mmol) inoxygen-free tetrahydrofuran (100 mL) is added diisopropylamine (3.68 g,0.0285 mol) 5-chloromethyl-6-hydroxy-2,3,4-trihydronaphthalen-1-one,prepared as described in Chem. Pharm. Bull. 1977;25(11):2988-3002 (6.0g, 0.0285 mol) is dissolved in tetrahydrofuran (125 mL) and the solutionadded dropwise to the preceding solution at 25° C. over 45 minutes. Themixture is stirred for 22 hours, concentrated in vacuo, and the residuelayered with ethyl ether. Water is added to the mixture giving a solidprecipitate. The solid is filtered, washed with water, and dried at 25°C. The solid is recrystallized from ethyl acetate and dried in vacuogiving a white solid (7.3 g, 75% yield). MS: APCI: M+1: 343.1 (M:342.41). NMR spectrum is consistent with the structure.

[0510] 2. Methyl2-{[2-((1S)-24-Imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]methylthio}benzoate

[0511] (R)-2-Imidazol-1-yl-1-phenyl-ethanol (2.42 g, 12.9 mmol),triphenylphosphine (4.60 g, 17.5 mmol), and2-(2-hydroxy-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethylsulfanyl)-benzoicacid methyl ester (4.0 g, 11.7 mmol) are suspended in drytetrahydrofuran (250 mL). To the suspension is added a solution ofdiethyl azodicarboxylate (3.05 g, 17.5 mmol) in tetrahydrofuran (50 mL)over 30 minutes. After stirring for 18 hours at 25° C., the mixture isevaporated to a syrup in vacuo. The residue is added to ethyl ether and1N citric acid, which subsequently gives a solution. The ether phase isdecanted from the mixture, and the citric acid phase is washedexhaustively with ethyl ether. The citric acid phase is layered withethyl acetate, and the pH of the citric acid phase is adjusted to 13with 6N NaOH giving a yellow oily precipitate. The oil is dissolved inchloroform, washed with brine, dried over anhydrous magnesium sulfateand filtered. The filtrate is evaporated in vacuo to a foam. The productis purified by chromatography on 200 g silica gel eluted withchloroform/1% methanol. The product (Compound 4) is obtained fromchloroform/ethyl ether as a foam (1.88 g, 31% yield). MS: APCI: M+1:513.2 (M: 512.6). NMR spectrum is consistent with structure.

[0512] Calcd. For C₃₀H₂₈N₂O₄S.0.23 CHCl₃, 0.275H₂O:

[0513] Theory: C, 67.31; H, 5.27; N, 5.20; Cl, 3.36, H₂O, 1.00.

[0514] Found: C, 67.21; H, 5.38; N, 4.72; Cl, 3.42, H₂O, 1.12.

EXAMPLE 5

[0515] Synthesis of2-{[2-((1S)-2-Imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphenyl]methylthio}benzoicAcid (Compound 5)

[0516] To dioxane (20 mL) is added compound 4 (0.5 g, 0.975 mmol),followed by the addition of a 1N solution of NaOH (3.0 mL). After themixture is stirred for 72 hours, the dioxane is evaporated in vacuo, andthe residue is washed twice with ethyl ether. The residue is layeredwith ethyl ether and acidified with 1N HCl to pH 4 giving a solidprecipitate. The ether is removed from the suspension in vacuo, and theresidue is taken up in dichloromethane giving a two phase solution. Thedichloromethane phase is dried over anhydrous magnesium sulfate,filtered, and evaporated to an oil (325 mg). The oil is layered withethyl ether, and 1N NaOH is added. The pH is adjusted to 5 by additionof 1N HCl resulting in an off-white precipitate. The solid is filtered,dried and purified by silica gel chromatography and eluted withchloroform/methanol (90:10). A white solid (compound 5) is recovered(120 mg, 25% yield).

[0517] Calcd. for C₂₉H₂₆N₂O₄S, 0.23 CHCl₃, 0.6H₂O: Theory: C 65.40, H4.92, N 5.22, Cl 4.56, H₂O, 2.01. Found: C 65.24, H 5.12, N 5.23, Cl3.72, H₂O, 1.72.

EXAMPLE 6

[0518] Synthesis of6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-isopropylsulfanylmethyl-2,3,4-trihydronaphthalen-1-one(Compound 6)

[0519] 1.6-Hydroxy-5-isopropylsulfanylmethyl-2,3,4-trihydronaphthalen-1-one

[0520] Tetrahydrofuran (100 mL, anhydrous, distilled) is sparged withnitrogen gas followed by addition of triethylamine (6.97 mL, 50 mmol)and 2-propanethiol (7 mL, 150 mmol). A solution of5-chloromethyl-6-hydroxy-2,3,4-trihydronaphthalen-1-one, prepared asdescribed in Chem. Pharm. Bull. 1977;25(11):2988-3002 (10.53 g, 50 mmol)in tetrahydrofuran (175 mL) is added. The mixture is stirred for 1 hourat 25° C. followed by heating at 85° C. for 3 hours. The mixture isfiltered and the filtrate is evaporated under vacuum giving a solid. Thesolid is dissolved in ethyl acetate and then washed with 1N citric acidand brine. The organic phase is separated, dried over anhydrousmagnesium sulfate and filtered. The filtrate is concentrated in vacuogiving a solid which is filtered, washed with ethyl ether, and dried invacuo to a solid (8.69 g, 69.4% yield). NMR spectrum is consistent withstructure. MS: APCI: M+1: 251.2 (M: 250.4).

[0521] 2.6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-54-isopropylsulfanylmethyl-2,3,4-trihydronaphthalen-1-one

[0522] (R)-2-Imidazol-1-yl-1-phenyl-ethanol (3.05 g, 21.1 mmol),triphenylphosphine (5.54 g, 21.1 mmol), and6-hydroxy-5-isopropylsulfanyl methyl-2,3,4-trihydronaphthalen-1-one (3.5g, 14 mmol) are suspended in dry tetrahydrofuran (75 mL). To thesuspension is added a solution of diethyl azodicarboxylate (3.68 g, 21.1mmol) in tetrahydrofuran (30 mL) over 30 minutes at 25° C. Afterstirring for 3 hours at 25° C., the mixture is evaporated to a solid invacuo. To the residue is added ethyl ether and 1N citric acid whichgives a precipitate. The ether phase is decanted from the mixture andthe mixed precipitate and citric acid phases are washed exhaustivelywith ethyl ether. The citric acid phase is layered with ethyl ether andthe pH of the citric acid phase is adjusted to 5.5 with 6N NaOH. Theproduct is extracted into a mixture of ethyl acetate and ethyl ether,washed with brine, dried over anhydrous magnesium sulfate and filtered.The filtrate is concentrated in vacuo and is purified by chromatographyon 150 g silica gel eluted with a gradient of chloroform to 2% methanol.The product (Compound 6) is obtained as a solid (3.12 g, 53% yield). MS:APCI: M+1: 425.1 (M: 420.6). NMR spectrum is consistent with structure.Calcd. for C₂₅H₂₈N₂O2S, 0.125 CHCl₃, 0.0125H₂O: Theory: C 69.26, H 6.15,N 6.43, Cl 3.05, H₂O 0.52. Found: C 69.12, H 6.61, N 6.38, Cl 2.85, H₂O0.51.

EXAMPLE 7

[0523] Synthesis of6-(1S)-2-Imidazolyl-1-phenylethoxy)-5-{[(methylethyl)sulfonyl]methyl}-2,3,4-trihydronaphthalen-1-one(Compound 7)

[0524] 1.6-Hydroxy-5-isopropylsulfonylmethyl-2,3,4-trihydronaphthalen-1-one

[0525] To dichloromethane (100 mL) is added6-hydroxy-5-isopropylsulfanyl methyl-2,3,4-trihydronaphthalen-1-one,(3.74 g, 14.9 mmol). The mixture is cooled to 15° C., followed by theaddition of m-chloroperbenzoic acid (70% with water, 7.36 g, 29.9 mmol)over 2 minutes. The mixture is stirred for 5 hours at 25° C. giving asuspended solid. The suspension is evaporated under vacuum. Theresulting solid is dissolved in warm ethyl acetate (700 mL) and washedwith saturated sodium bicarbonate and brine. The organic phase isseparated, dried over anhydrous magnesium sulfate and filtered. Thefiltrate is concentrated in vacuo to 150 mL in volume at 2° C. giving asuspended solid. The solid is filtered, washed with ethyl ether, anddried in vacuo (2.64 g, 63% yield). NMR spectrum is consistent withstructure. MS: APCI: M+1: 283.0 (M: 282.36).

[0526] 2.6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[(methylethyl)sulfonyl]methyl}-2,3,4-trihydronaphthalen-1-one

[0527] (R)-2-Imidazol-t-yl-1-phenyl-ethanol (1.95 g, 10.3 mmol),triphenylphosphine (3.54 g, 13.5 mmol), and6-hydroxy-5-isopropylsulfonylmethyl-2,3,4-trihydronaphthalen-1-one (2.54g, 9.0 mmol) are suspended in dry tetrahydrofuran (50 mL). To thesuspension is added a solution of diethyl azodicarboxylate (2.35 g, 13.5mmol) in tetrahydrofuran (20 mL) over 30 minutes at 25° C. Afterstirring for 5 hours at 25° C., the mixture is evaporated in vacuo. Tothe residue is added ethyl ether and 1N citric acid which gives aprecipitate. The ether phase is decanted from the mixture and the mixedprecipitate and citric acid phases are washed exhaustively with ethylether. The citric acid phase and the suspended oil are layered withethyl acetate and the pH of the citric acid phase is adjusted to 6.5with 6N NaOH. The product is extracted into the ethyl acetate, washedwith brine, dried over anhydrous magnesium sulfate and filtered. Thefiltrate is concentrated in vacuo and is purified by chromatography on150 g silica gel eluted with a gradient of chloroform to 2% methanol.The product (Compound 7) is obtained as a solid (3.12 g, 53% yield). MS:APCI: M+1 (M: 452.58). NMR spectrum is consistent with structure.

[0528] Calcd. for C₂₅H₂₈N₂O₄S, 0.125 CHCl₃, 0.0125H₂O: Theory: C 69.26,H 6.15, N 6.43, Cl 3.05, H₂O 0.52. Found: C 69.12, H 6.61, N 6.38, Cl2.85, H₂O 0.51.

EXAMPLE 8

[0529] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(4-pyridylthiomethyl)-2,3,4-trihydronaphthalen-1-one(Compound 8)

[0530] 1.6-Hydroxy-5-(pyridin-4-ylsulfanylmethyl)-2,3,4-trihydronaphthalen-1-one

[0531] To tetrahydrofuran (50 mL) is added 4-mercaptopyridine (3.33 g,30 mmol) and triethylamine (2.08 mL, 15 mmol). The mixture is warmed to30° C., followed by the addition of a solution of5-chloromethyl-6-hydroxy-2,3,4-trihydronaphthalen-1-one, prepared asdescribed in Chem. Pharm. Bull. 1977;25(11):2988-3002 (2.11 g, 10 mmol)in tetrahydrofuran (25 mL) giving a suspension. The mixture is stirredfor 18 hours at 55° C. The suspension is filtered, and the filtrate isevaporated under vacuum giving a solid. The solid is dissolved in 1NNaOH (100 mL), washed with ethyl ether, and separated. The pH of theaqueous phase is adjusted to 10 with 6N HCl giving a solid precipitate.The suspension is with ethyl acetate, washed with minimal amounts ofwater, brine, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate is concentrated in vacuo to a small volume, giving a suspendedsolid. The solid is filtered, washed with ethyl acetate, and dried invacuo to give desired product (1.42 g, 49.8% yield). NMR spectrum isconsistent with structure. MS: APCI: M+1: 286.1 (M: 285.37).

[0532] 2.6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(4-pyridylthiomethyl)-2,3,4-trihydronaphthalen-1-one

[0533] (R)-2-Imidazol-1-yl-1-phenyl-ethanol (1.03 g, 5.47 mmol),triphenylphosphine (1.87 g, 7.13 mmol), and6-hydroxy-5-(pyridin-4-yl-sulfanylmethyl)-2,3,4-trihydronaphthalen-1-one(1.35 g, 4.73 mmol) are suspended in dry tetrahydrofuran (25 mL). To thesuspension is added a solution of diethyl azodicarboxylate (1.24 g, 4.73mmol) in tetrahydrofuran (10 mL) over 30 minutes at 25° C. Afterstirring for 3 hours at 25° C., the mixture is evaporated in vacuo. Theresidue is added to ethyl ether and 1N citric acid. The ether phase isdecanted from the mixture, and the mixed precipitate and citric acidphases are washed exhaustively with ethyl ether. The citric acid phaseand the suspended oil are layered with a mixture of ethyl acetate andethyl ether, and the pH of the citric acid phase is adjusted to 6.5 with6N NaOH giving an oily precipitate. The product is dissolved into theorganic phase by addition of ethyl acetate, washed with brine, driedover anhydrous magnesium sulfate, and filtered. The filtrate isconcentrated in vacuo and is purified by chromatography on 100 g silicagel eluted with a gradient of chloroform to 5% methanol. The product(Compound 8) is obtained as a solid (1.5 g, 49.8% yield). MS: APCI: M+1,456.3 (M: 455.6). NMR spectrum is consistent with structure.

[0534] Calcd. for C₂₇H₂₅N₃O₂S, 0.125 CHCl₃, 0.1H₂O: Theory: C 68.98, H5.40, N 8.89, Cl 2.81, H₂O 0.38. Found: C 68.87, H 5.62, N 9.08, Cl3.16, H₂O 0.68.

EXAMPLE 9

[0535] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-pyridylthiomethyl)-2,3,4-trihydronaphthalen-1-one(Compound 9)

[0536] 1.6-Hydroxy-5-(pyridin-2-ylsulfanylmethyl)-2,3,4-trihydronaphthalen-1-one

[0537] To tetrahydrofuran (500 mL) is added 2-mercaptopyridine (16 g,0.14 mol) and triethylamine (20.8 mL, 0.15 mol). The mixture is warmedto 30° C., followed by the addition of a solution of5-chloromethyl-6-hydroxy-2,3,4-trihydronaphthalen-1one, prepared asdescribed in Chem. Pharm. Bull. 1977;25(11):2988-3002 (29.5 g, 0.143mol) in tetrahydrofuran (300 mL) giving a suspension. The mixturestirred for 18 hours at 25° C. The suspension is filtered, and thefiltrate is evaporated under vacuum giving a solid. The solid isdissolved in warm ethyl acetate, washed with 300 mL of water and thenbrine, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate is concentrated in vacuo to a small volume, giving a suspendedsolid. The solid is filtered, washed with ethyl acetate, and dried invacuo to afford product (22.26 g, 56% yield). NMR spectrum is consistentwith structure. MS: APCI: M+1: 286.1 (M: 285.4).

[0538] 2.6-[(S)-2-(2,5-Dihydro-imidazol-1-yl)-1-phenyl-ethoxy]-5-(pyridin-2-ylsulfanylmethyl)-2,3,4-trihydronaphthalen-1-one

[0539] (R)-2-Imidazol-1-yl-1-phenyl-ethanol (1.80 g, 9.6 mmol),triphenylphosphine (3.27 g, 12.5 mmol), and6-hydroxy-5-(pyridin-2-yl-sulfanylmethyl)-2,3,4-trihydronaphthalen-1-one(2.36 g, 8.29 mmol) are suspended in dry tetrahydrofuran (45 mL). To thesuspension is added a solution of diethyl azodicarboxylate (2.18 g, 12.5mmol) in tetrahydrofuran (20 mL) over 30 minutes at 25° C. Afterstirring for 3 hours at 25° C., the mixture is evaporated in vacuo. Tothe residue is added ethyl ether and 1N citric acid. The ether phase isdecanted from the mixture, and the mixed precipitate and citric acidphases are washed exhaustively with ethyl ether. The citric acid phaseand the suspended oil are layered with a mixture of ethyl acetate andethyl ether, and the pH of the citric acid phase is adjusted to 9 with6N NaOH giving an oily precipitate. The product is dissolved into theorganic phase by addition of ethyl acetate, washed with brine, driedover anhydrous magnesium sulfate, and filtered. The filtrate isconcentrated in vacuo and is purified by chromatography on 100 g silicagel eluted with a gradient of chloroform to 5% methanol. The product(Compound 9) is obtained as a solid (1.5 g, 49.8% yield). MS: APCI: M+1,456.3 (M: 455.6). NMR spectrum is consistent with structure.

[0540] Calcd. for C₂₇H₂₅N₃O₂S, 0.125 CHCl₃, 0.1H₂O: Theory: C 68.98, H5.40, N 8.89, Cl 2.81, H₂O 0.38. Found: C 68.87, H 5.62, N 9.08, Cl3.16, H₂O 0.68.

EXAMPLE 10

[0541] Synthesis of6-(1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-pyridylsulfonyl)methyl]-2,3,4-trihydronaphthalen-1-one hydrochloride (Compound 10)

[0542] 1.6-Hydroxy-5-(pyridine-2-sulfonylmethyl)-3,4-dihydro-2H-naphthalen-1-one

[0543]6-Hydroxy-5-(pyridin-2-ylsulfanylmethyl)-2,3,4-trihydronaphthalen-1-one(18 g, 0.063 mol) is added to dichloromethane (400 mL). A solution ofm-chloroperbenzoic acid (70%, 33.6 g, 0.136 mol) in dichloromethane (250mL) is added over 2 hours, after which the mixture is allowed to stirfor 18 hours at 25° C. The mixture is filtered, and the solid isresuspended in hot ethyl acetate and extracted with saturated sodiumbicarbonate solution. The organic phase is washed with brine, dried overanhydrous magnesium sulfate, and filtered. The filtrate is concentratedgiving a solid, which is subsequently filtered, washed with ethylacetate and dried, 6.8 g, 34% yield. MS: APCI: M+1, 318.3 (M: 317.4).NMR spectrum is consistent with structure.

[0544] 2.6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-pyridylsulfonyl)methyl]-2,3,4-trihydronaphthalen-1-one

[0545] (R)-2-Imidazol-1-yl-1-phenyl-ethanol (1.80 g, 9.6 mol),triphenylphosphine (3.27 g, 12.5 mmol), and6-hydroxy-5-(pyridine-2-sulfonylmethyl)-3,4-dihydro-2H-naphthalen-1-one(2.63 g, 8.29 mmol) are suspended in dry tetrahydrofuran (50 mL). To thesuspension is added a solution of diethyl azodicarboxylate (2.18 g, 12.5mmol) in tetrahydrofuran (20 mL) over 40 minutes at 25° C. Afterstirring for 68 hours at 25° C., the mixture is evaporated in vacuo. Theresidue is added to ethyl ether and 1N citric acid. The ether phase isdecanted from the mixture, and the mixed precipitate and citric acidphases are washed exhaustively with ethyl ether. The citric acid phaseis layered with a mixture of ethyl acetate and ethyl ether, and the pHof the citric acid phase is adjusted to 8 with 6N NaOH giving an oilyprecipitate. The product is dissolved into the organic phase by additionof ethyl acetate, washed with brine, dried over anhydrous magnesiumsulfate, and filtered. The filtrate is concentrated in vacuo and ispurified by chromatography on 100 g silica gel eluted with a gradient ofchloroform to 5% methanol. The product is obtained as a solid 1.0 g, 43%yield. MS: APCI: M+1, 488.2 (M: 487.5). The product was stirred with oneequivalent of 1M HCl solution in ether. The solution was concentratedand the hydrochloride (Compound 10) was collected by filtration. NMRspectrum is consistent with structure.

[0546] Calcd. for C₂₂H₂₅N₃O₂S, 0.125 CHCl₃, 0.1H₂O: Theory: C 68.98, H5.40, N 8.89, Cl 2.81, H₂O 0.38. Found: C 68.87, H 5.62, N 9.08, Cl3.16, H₂O 0.68.

EXAMPLE 10a

[0547]

[0548] Synthesis of6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(naphthalen-1-ylsulfanylmethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 10a)

[0549] 1.6-Hydroxy-5-(naphthalen-1-ylsulfanylmethyl)-3,4-dihydro-2H-naphthalen-1-one

[0550] To a solution of 1-naphthalenethiol (19.38 g, 0.092 mol) inoxygen-free tetrahydrofuran (500 ml) was added diisopropylamine (12.74g, 0.098 mol). 5-Chloromethyl-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one,prepared as described Chem. Pharm. Bull. 25(11)2988-3002(1977), (6.0 g,0.0285 mol) was dissolved in tetrahydrofuran (300 ml) and the solutionadded dropwise to the preceding solution at 25° C. over 2 hours. Themixture was stirred for 16 hours, concentrated in vacuo and the residuelayered with ethyl acetate. The suspension was filtered and washed withhot chloroform, a small amount of ethyl ether, 1N citric acid and water.The solid was dried in vacuo at 70° C. giving a solid, 18.5 g, 59%yield. MS: APCI: M+1: 335.0 (M: 334.4).

[0551] 2.6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(naphthalen-1-ylsulfanylmethyl)-3,4-dihydro-2H-naphthalen-1-one

[0552] In a manner similar to that of Example 7, step(b),(R)-2-Imidazol-1-yl-1-phenyl-ethanol (0.565 g, 3.0 mmol) and6-Hydroxy-5-(naphthalen-1-ylsulfanylmethyl)-3,4-dihydro-2H-naphthalen-1-one(0.84 g, 2.5 mmol) gave a solid, 0.79 g, 62% yield. MS: APCI: M+1: 505.1(M: 504.7). Calcd. For C32H28N2O2S 0.05CHCl3: Theory: C, 75.38; H, 5.54;N, 5.48; Cl, 0.10 Found: C, 75.67; H, 5.81; N, 5.41; Cl, 0.35.

EXAMPLE 10b

[0553] Synthesis of[2-(2-Imidazol-1-yl-1(S)-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethylsulfanyl]-aceticacid methyl ester (Compound 10b)

[0554] 1.(2-Hydroxy-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethylsulfanyl)aceticacid methyl ester

[0555] 5-Chloromethyl-6-hydroxy-1-tetralone (315 mg, 1.5 mmol) andmethyl thioglycolate (2.0 mL, 22 mmol) were combined in a septum cappedround bottomed flask and heated to 40° C. overnight. The excess methylthioglycolate was removed in vacuo and the pot residue was purified bysilica gel chromatography (R_(f)=0.18, hexanes/ethyl acetate/aceticacid, 58:40:2) to give 219 mg (52%) of the desired compound as acolorless glass: ¹H NMR (CDCl₃) δ 2.02 (p, 2H, J=6.01 Hz); 2.50 (t, 2H,J=6.01 Hz); 2.89 (t, 2H, J=6.01 Hz); 3.19 (s, 2H); 3.64 (s, 3H); 3.85(s, 2H); 6.79 (d, 1H, J=8.7 Hz); 7.83 (d, 1H, J=8.7 Hz); 8.59 (br s,1H).

[0556] 2.[2-(2-Imidazol-1-yl-[(S)-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethylsulfanyl]-aceticAcid Methyl Ester

[0557](2-Hydroxy-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethylsulfanyl)-aceticacid methyl ester (200 mg, 0.71 mmol),(R)2-imidazol-1-yl-1-phenyl-ethanol (141 mg, 0.75 mmol), andtriphenylphosphine resin (1.5 g, loading 1.41 mmol/g) were combined indry tetrahydrofuran (10 mL) and treated with diethyl azodicarboxylate(337 μL, 2.1 mmol). The resulting orange-brown heterogeneous mixture wasallowed to stir at ambient temperature overnight. The spenttriphenylphosphine resin was removed by filtration, washing sequentiallywith ethyl acetate, methanol, and chloroform. The filtrate wasconcentrated in vacuo and the crude material was purified by silica gelchromatography (hexanes/ethyl acetate/triethylamine 20:75:5) to give 84mg (26%) of the desired product as a light yellow glass: (LC-MS, APCI)m/z 450 M+H]⁺; ¹H NMR (CDCl₃) δ 2.10 p, 2H, J=6.01 Hz); 2.54 (t, 2H,J=6.01 Hz); 3.02 (t, 2H, J=6.01 Hz); 3.37 (s, 2H); 3.75 (s, 3H); 4.06(apparent q, 2H); 4.40 (dd, 1H, J=11.1, 3.0 Hz); 4.50 (dd, 1H, J=11.1,5.4 Hz); 5.46 (dd, 1H, J=5.4, 3.0 Hz); 6.52 (d, 1H, J=6.6 Hz); 6.97 (s,1H); 7.02 (s, 1H); 7.25-7.36 (m, 6H); 7.51 (s, 1H); 7.80 (d, 1H, J=6.6Hz); ¹³C NMR (CDCl₃) 22.6, 26.1, 27.9, 34.1, 38.2, 52.4, 53.1, 79.5,111.3, 119.7, 123.0, 125.9, 127.1, 128.6, 128.9, 129.2, 129.4, 136.6,137.9, 145.3, 158.6, 170.9, 197.1.

EXAMPLE 10c

[0558] Synthesis of5-(3,4-Dichloro-benzylsulfanylmethyl)-6-((1S)-2-imidazol-1-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one(Compound 10c)

[0559] 1.5-(3,4-Dichloro-benzylsulfanylmethyl)-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one

[0560] 5-Chloromethyl-6-hydroxy-1-tetralone (315 mg, 1.5 mmol) and(3,4-Dichloro-phenyl)-methanethiol (1.0 mL, 6.0 mmol) were sealed in a16×120 mm screw capped tube and heated to 40° C. overnight. The excess(3,4-Dichloro-phenyl)-methanethiol was removed in vacuo and the residuewas purified by silica gel chromatography (hexanes/ethyl acetate/aceticacid, 58:40:2) to give 350 mg (63%) of the desired product as a tanpowder: (LC-MS, APCI) m/z 367/369 [M+H]⁺.

[0561] 2.5-(3,4-Dichloro-benzylsulfanylmethyl)-6-((1S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one

[0562]5-(3,4-Dichloro-benzylsulfanylmethyl)-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one(256 mg, 0.69 mmol), (R)-2-imidazol-1-yl-1-phenyl-ethanol (144 mg, 0.75mmol), and triphenylphosphine resin (1.46 g, loading 1.41 mmol/g) werecombined in dry tetrahydrofuran (10 mL) and treated with diisopropylazodicarboxylate (271 μL, 2.0 mmol). The resulting orange-brownheterogeneous mixture was allowed to stir at ambient temperatureovernight. The spent triphenylphosphine resin was removed by filtration,washing sequentially with ethyl acetate, methanol, and chloroform. Thefiltrate was concentrated in vacuo and the crude material was purifiedby silica gel chromatography (hexanes/ethyl acetate/triethylamine28:70:2) to give 280 mg (75%) of the desired product as a colorlesssolid: (LC-MS, APCI) m/z 553/555 [M+H]⁺.

EXAMPLE 10d

[0563]

[0564] Synthesis of (S)-6-552-[2-(Hydroxymethyl)-1H-imidazol-1-yl]-1-phenylethoxy{-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone(Compound 10d)

[0565] A mixture of(S)-6-[2-(1H-imidazol-1-yl)-1-phenylethoxy]-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone(see example 3, 250 mg, 0.51 mmol), paraformaldehyde (1.5 g) anddimethylsulfoxide (6 mL) was stirred at 130° C. for 24 h. The mixturewas diluted with ethanol (10 mL), filtered, concentrated, diluted withwater (50 mL) and extracted with ethyl acetate (4×10 mL). The combinedextracts were washed with water (3×10 mL), dried (brine, Na₂SO₄), andconcentrated. The residue was purified by dry-flash columnchromatography (SiO₂, 2.5-22.5% 2-propanol-dichloromethane) to give(S)-6-{2-[2-(hydroxymethyl)-1H-imidazol-1-yl]-1-phenylethoxy}-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenoneas a white solid, 161 mg, 61% yield. NMR spectrum was consistent withstructure. MS EI: M^(+•) 517.1816 (M^(+•) 517.1797).

EXAMPLE 11

[0566] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(phenylamino)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 11)

[0567] 1. 6-Hydroxy-5-phenylaminomethyl-2,3,4-trihydronaphthalen-1-one

[0568] To a solution of aniline (13.27 g, 0.1425 mol) in tetrahydrofuran(100 mL) is added a solution of5-chloromethyl-6-hydroxy-2,3,4-trihydronaphthalen-1-one (Chem. Pharm.Bull. 1977;25(11):2988-3002) (6.0 g, 0.0285 mol) in tetrahydrofuran (150mL) at 25° C. The mixture is stirred for 3 hours, concentrated in vacuoand the residue layered with ethyl ether. The mixture is extracted with1N citric acid and the ether layer is washed with brine. Upon standing,a solid precipitates from the organic phase. The ether is concentratedin vacuo and the solid is filtered and dried in vacuo giving 4.47 g (59%yield). MS: APCI: M+1: 268.1 (M: 267.3). NMR spectrum is consistent withstructure.

[0569] 2.6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(phenylamino)methyl]-2,3,4-trihydronaphthalen-1-one

[0570] (R)-2-Imidazol-1-yl-1-phenyl-ethanol (3.42 g, 18.2 mmol),triphenylphosphine (6.49 g, 24.8 mmol), and6-hydroxy-5-phenylaminomethyl-2,3,4-trihydronaphthalen-1-one (4.4 g,16.5 mmol) are suspended in dry tetrahydrofuran (250 mL). To thesuspension is added a solution of diethyl azodicarboxylate (4.31 g, 24.8mmol) in tetrahydrofuran (50 mL) over 45 minutes. After stirring for 18hours at 25° C., the mixture is evaporated to a syrup in vacuo. To theresidue is added ethyl ether and 1N citric acid. The ether phase isdecanted from the mixture, and the citric acid phase is washedexhaustively with ethyl ether. The citric acid phase is layered withethyl acetate, and the pH of the citric acid phase is adjusted to 13with 6N NaOH giving a yellow solid precipitate. The solid is dissolvedby addition of chloroform, washed with brine, dried over anhydrousmagnesium sulfate, and filtered. The filtrate is concentrated in vacuoand crystallized by addition of ethyl ether. The solid is filtered,washed with ethyl ether and dried giving a solid, 6.95 g, 96% yield. Theproduct is purified by chromatography on 200 g silica gel eluted withchloroform/1% methanol. The product (Compound 11) is obtained fromchloroform/ethyl ether as a brittle foam (1.5 g, 21% yield). NMRspectrum is consistent with structure.

[0571] Calcd. for C₂₈H₂₇N₃O₂S 0.075 CHCl₃, 0.15H₂O: Theory: C 75.07, H6.08, N 9.35, Cl 1.78, H₂O, 0.60. Found: C 75.02, H 6.24, N 9.32, Cl1.52, H₂O, 0.57.

EXAMPLE 12

[0572] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(methylphenylamino)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 12)

[0573] 1.6-Hydroxy-5-[(methyl-phenylamino)methyl]-2,3,4-trihydronaphthalen-1-one

[0574] To a solution of n-methylaniline (3.81 g, 0.0356 mol) intetrahydrofuran (80 mL) is added a solution of5-chloromethyl-6-hydroxy-2,3,4-trihydro-naphthalen-1-one (Chem. Pharm.Bull. 1977;25(11):2988-3002) (2.5 g, 0.0119 mol) in tetrahydrofuran (80mL) at 25° C. over 30 minutes. The mixture is concentrated in vacuo andis extracted with 1N citric acid. The aqueous phase is layered withethyl ether and the pH is adjusted to 10 with 1N NaOH. The product isextracted into the ethyl ether phase, washed with brine, dried overanhydrous magnesium sulfate and filtered. Upon concentration of thefiltrate in vacuo, a solid precipitates from the organic phase. Thesolid is filtered and dried in vacuo giving a white solid (3.33 g, 67%yield). MS: APCI: M+1: 282.1 (M: 281.3). NMR spectrum is consistent withstructure.

[0575] 2.6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(methyl-phenylamino)methyl]-2,3,4-trihydronaphthalen-1-one

[0576] (R)2-Imidazol-1-yl-1-phenyl-ethanol (2.28 g, 12.1 mmol),triphenylphosphine (4.17 g, 15.9 mmol), and6-hydroxy-5-[(methyl-phenyl-amino)-methyl]-2,3,4-trihydronaphthalen-1-one(3.0 g, 10.7 mmol) are suspended in dry tetrahydrofuran (50 mL). To thesuspension is added a solution of diethyl azodicarboxylate (2.77 g, 15.9mmol) in tetrahydrofuran (25 mL) over 2 hours at 25° C. After stirringfor 2 hours at 25° C., the mixture is evaporated to a foam in vacuo. Tothe residue is added ethyl ether and 1N citric acid. The ether phase isdecanted from the mixture and the citric acid phase is washedexhaustively with ethyl ether. The citric acid phase is layered withethyl acetate and the pH of the citric acid phase is adjusted to 12 with6N NaOH. The product is extracted into ethyl acetate, washed with brine,dried over anhydrous magnesium sulfate and filtered. The filtrate isconcentrated in vacuo and is purified by chromatography on 200 g silicagel eluted with chloroform/1% methanol. The product is obtained fromethyl ether as a brittle foam, which become a glass (Compound 12) upondrying in vacuo at 65° C. (2.4 g, 50% yield). MS: APCI: M+1: 452.1 (M:451.6). NMR spectrum is consistent with structure.

[0577] Calcd. for C₂₉H₂₉N₃O₂S 0.1 CHCl₃: Theory: C 75.41, H 6.33, N9.07, Cl 2.29, H₂O, 0.00. Found: C 75.11, H 6.41, N 9.09, Cl 1.83, H₂O,0.34.

EXAMPLE 13

[0578] Synthesis of Methyl4-({[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo(6,7,8-trihydronaphthyl)]methyl}methylamino)benzoate(Compound 13)

[0579] 1. Methyl4-[(2-Hydroxy-5-oxo-5,6,7,8-tetrahydronaphthalen-1-ylmethyl)methyl-amino]benzoate

[0580] To a solution of methyl-4(methylamino)benzoate (5.88 g, 0.0356mol) in tetrahydrofuran (80 mL) is added a solution of5-chloromethyl-6-hydroxy-2,3,4-trihydronaphthalen-1-one (Chem. Pharm.Bull. 1977;25(11):2988-3002) (2.5 g, 0.0119 mol) in tetrahydrofuran (80mL) at 25° C. over 30 minutes. After stirring for 18 hours, the mixtureis concentrated in vacuo, taken up in ethyl ether, and washed with 1Ncitric acid. A solid precipitates from the organic phase, which isfiltered and dried in vacuo giving a white solid (2.16 g, 54% yield).MS: APCI: M11: 338.1 (M: 339.4). NMR spectrum is consistent withstructure.

[0581] 2. Methyl4-({[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo(6,7,8-trihydronaphenyl)]methyl}methylamino)benzoate

[0582] (R)-2-Imidazol-1-yl-1-phenyl-ethanol (1.22 g, 6.48 mmol),triphenyl-phosphine (2.32 g, 8.84 mmol), and4-[(2-hydroxy-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl)-methyl-amino]-benzoicacid methyl ester (2.0 g, 5.89 mmol) are suspended in drytetrahydrofuran (85 mL). To the suspension is added a solution ofdiethyl azodicarboxylate (1.54 g, 8.84 mmol) in tetrahydrofuran (25 mL)over 30 minutes at 25° C. After stirring for 18 hours at 25° C., themixture is evaporated to an oil in vacuo. To the residue is added ethylether and 1N citric acid. The ether phase is decanted from the mixture,and the citric acid phase is washed exhaustively with ethyl ether. Thecitric acid phase is layered with ethyl ether, and the pH of the citricacid phase is adjusted to 13 with 6N NaOH. The product is extracted intoethyl ether, washed with brine, dried over anhydrous magnesium sulfate,and filtered. The filtrate is concentrated in vacuo and is purified bychromatography on 200 g silica gel eluted with chloroform/1% methanol.The product is obtained from ethyl ether as a solid (Compound 13) (1.33g, 44% yield). MS: APCI: M+1: 510.2 (M: 509.6). NMR spectrum isconsistent with structure.

[0583] Calcd. for C₃₁H₃₁N₃O₄S 0.05 CHCl₃, 0.05H₂O: Theory: C 72.09, H6.05, N 8.14, Cl 1.03, H₂O, 0.17. Found: C 71.88, H 6.08, N 8.01, Cl0.95, H₂O, 0.37.

EXAMPLE 14

[0584] Synthesis of4-({[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo(6,7,8-trihydronaphthyl)]methyl}methylamino)benzoicacid, 2,2,2-trifluoroacetic acid (Compound 14)

[0585] To a mixture of dioxane (10 mL) and water (10 mL) is added methyl4-({[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo(6,7,8-trihydronaphthyl)]methyl}methylamino)benzoate(Compound 13) (1.10 g, 2.16 mmol) and 1N NaOH (9 mL). The mixture isstirred at 25° C. for 18 hours, and the dioxane is removed in vacuo. Themixture is layered with ethyl ether and acidified by the addition of 1NHCl (9 mL). The resulting solid precipitate is filtered, washed withethyl ether, and dried at 25° C. The solid is purified by reverse phasechromatography, eluting with acetonitrile/water, 0.1% trifluoroaceticacid. The product is recovered as a foam (Compound 14) (175 mg, 16.3%yield). NMR spectrum is consistent with structure.

[0586] Calcd. for C₃₀H₂₉N₃O₄ 1.3 TFA, 0.75H₂O: Theory: C 59.57, H 4.88,N 6.39, H₂O, 2.05. Found: C 59.34, H 4.76, N 6.23, H₂O, 1.29.

EXAMPLE 15

[0587] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(methylethoxy)methyl]-2,3,4-trihydronaphthalen-1-onehydrochloride (Compound 15)

[0588] 1. 6-Hydroxy-5-isopropoxymethyl-2,3,4-trihydronaphthalen-1-one

[0589] To a solution of diisopropylamine (6.46 g, 0.05 mol) inisopropanol (250 mL) is added5-chloromethyl-6-hydroxy-2,3,4-trihydronaphthalen-1-one (Chem. Pharm.Bull. 1977;25(11):2988-3002) (10.53 g, 0.05 mol). After stirring for 3hours at 100° C. followed by stirring at 25° C. for 18 hours, themixture is concentrated in vacuo and taken up in a mixture of ethylether, ethyl acetate, and 1N citric acid. The mixture is filteredthrough celite to remove a small amount of insoluble material. Theorganic phase is separated, washed with saturated sodium bicarbonatesolution and then brine, and dried over anhydrous magnesium sulfate. Theorganic phase is filtered and the filtrate is concentrated in vacuo.Upon concentration in vacuo, solid precipitates from the organic phase,which is filtered and dried in vacuo giving a white solid. Repeatedcrystallization gives a pure solid (6.64 g, 57% yield). NMR spectrum isconsistent with structure.

[0590] 2.6-((1S)-2-imidazolyl-1-phenylethoxy)-5-[(methylethoxy)methyl]-2,3,4-trihydronaphthalen-1-one

[0591] (R)-2-Imidazol-1-yl-1-phenyl-ethanol (3.05 g, 16.2 mmol),triphenylphosphine (5.54 g, 21.1 mmol), and6-hydroxy-5-isopropoxymethyl-2,3,4-trihydronaphthalen-1-one (3.3 g, 14mmol) are suspended in dry tetrahydrofuran (75 mL). To the suspension isadded a solution of diethyl azodicarboxylate (3.68 g, 21.1 mmol) intetrahydrofuran (30 mL) over 30 minutes at 30° C. After stirring for 18hours at 25° C., the mixture is evaporated to an oil in vacuo. To theresidue is added ethyl ether and 1N citric acid. The ether phase isdecanted from the mixture and the citric acid phase is washedexhaustively with ethyl ether. The citric acid phase is layered withethyl ether and the pH of the citric acid phase is adjusted to 5 with 2NNaOH. The product is extracted into ethyl ether, washed with 1N NaOH andbrine, dried over anhydrous magnesium sulfate and filtered. The filtrateis concentrated in vacuo and is purified by chromatography on 300 gsilica gel eluted with chloroform/2% methanol. The free base product isobtained from ethyl ether as a solid (4.92 g, 86% yield). MS: APCI: M+1:404.5 (M: 405.6). The hydrochloride salt is prepared by adding the freebase prepared above (2.0 g, 4.94 mmol) to 1N HCl (4.94 mL) giving asolution. The solution is diluted to 100 mL with deionized water,filtered, at 45 μ pore size, and lyophilized to a white solid (Compound15) (2.04 g, 94% yield). MS: APCI: M+1: 404.5 (M: 405.6). NMR spectrumis consistent with structure.

[0592] Calcd. for C₂₅H₂₈N₂O₃, 1.0 HCl, 0.5H₂O: Theory: C 66.81, H 6.78,N 6.22, Cl 7.58, H₂O, 2.28. Found: C 66.73, H 6.72, N 6.23, Cl 7.88,H₂O, 2.00.

EXAMPLE 16

[0593] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(phenylmethoxy)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 16)

[0594] 1. 5-Benzyloxymethyl-6-hydroxy-2,3,4-trihydronaphthalen-1-one

[0595] To benzyl alcohol (100 mL) is added5-chloromethyl-6-hydroxy-2,3,4-trihydronaphthalen-1-one (Chem. Pharm.Bull. 1977;25(11):2988-3002) (1.0 g, 4.75 mmol). After slightly warmingthe suspension, a solution occurs. To the mixture is added triethylamine(0.48 g, 4.75 mmol) followed by heating to 80° C. for 3 hours. Theexcess benzyl alcohol is distilled from the mixture under 2 mm Hg vacuumuntil the distillate temperature reaches 65° C. The residue is taken upin a mixture of ethyl ether and washed repeatedly with water. Theproduct is extracted into water by adjusting the pH to 12.5 by additionof 2N NaOH. The aqueous extract is washed with ethyl ether, layered withether and acidified by addition of 1N HCl. The organic phase isseparated, washed with brine, dried over anhydrous magnesium sulfate andfiltered. The filtrate is concentrated in vacuo giving a solid that isfiltered and dried in vacuo (1.12 g, 83% yield). NMR spectrum isconsistent with structure. MS: APCI: M+1: 282.3 (M: 283.1).

[0596] 2.6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(phenylmethoxy)methyl]-2,3,4-trihydronaphthalen-1-one

[0597] (R)-2-Imidazol-1-yl-1-phenyl-ethanol (0.733 g, 3.89 mmol),triphenyl-phosphine (1.39 g, 5.31 mmol), and5-benzyloxymethyl-6-hydroxy-2,3,4-trihydronaphthalen-1-one (1.0 g, 3.54mmol) are suspended in dry tetrahydrofuran (75 mL). To the suspension isadded a solution of diethyl azodicarboxylate (0.925 g, 5.31 mmol) intetrahydrofuran (20 mL) over 20 minutes at 25° C. After stirring for 18hours at 25° C., the mixture is evaporated to an oil in vacuo. To theresidue is added ethyl ether and 1N citric acid. The ether phase isdecanted from the mixture, and the citric acid phase is washedexhaustively with ethyl ether. The citric acid phase is layered withethyl ether and the pH of the citric acid phase is adjusted to 13 with2N NaOH. The product is extracted into a mixture of ethyl ether andchloroform, washed with brine, dried over anhydrous magnesium sulfate,and filtered. The filtrate is concentrated in vacuo and is purified bychromatography on 300 g silica gel eluted with chloroform. The productis further purified by reverse phase chromatography, eluted with amixture of acetonitrile, water, and 0.1% trifluoroacetic acid. Theproduct is obtained as a solid (Compound 16) (280 mg, 18% yield). MS:APCI: M+1: 452.6 (M: 453.3). NMR spectrum is consistent with structure.

[0598] Calcd. for C₂₉H₂₈N₂O₃, 1.25 TFA, 0.25H₂O: Theory: C 63.10, H5.00, N 4.67, F 11.88, H₂O, 0.75. Found: C 62.94, H 5.12, N 4.57, F11.49, H₂O, 0.62.

EXAMPLE 17

[0599] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(cyclopentyloxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 17)

[0600] 1.5-Cyclopentyloxymethyl-6-hydroxy-2,3,4-trihydronaphthalen-1-one

[0601] To cyclopentyl alcohol (30 mL) is added5-chloromethyl-6-hydroxy-2,3,4-trihydronaphthalen-1-one (Chem. Pharm.Bull. 1977;25(11):2988-3002) (1.0 g, 4.75 mmol). To the mixture is addedtriethylamine (3.5 mL, 23.7 mmol) followed by stirring for 3 hours at25° C. The excess cyclopentyl alcohol is distilled from the mixtureunder 2 mm Hg vacuum until the pot temperature reached 110° C. Theresidue is taken up in a mixture of ethyl acetate and ethyl ether andthen washed with 1N citric acid, water, and brine. The organic phase isseparated, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate is concentrated in vacuo giving an oil which is purified bysilica gel chromatography, eluted with a gradient of ethylacetate/hexane (5:95) to (20:80). The product is recovered as a solidfrom hexane, dried in vacuo (2.19 g, 28% yield). NMR spectrum isconsistent with structure. MS: APCI: M+1: 260.3 (M: 261.1).

[0602] 2.6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(cyclopentyloxymethyl)-2,3,4-trihydronaphthalen-1-one

[0603] (R)-2-Imidazol-1-yl-1-phenyl-ethanol (1.82 g, 9.67 mmol),triphenyl-phosphine (3.11 g, 11.9 mmol), and5-cyclopentyloxymethyl-6-hydroxy-2,3,4-trihydronaphthalen-1-one (2.06 g,8.79 mmol) are suspended in dry tetrahydrofuran (40 mL). To thesuspension is added a solution of diethyl azodicarboxylate (2.07 g, 11.9mmol) in tetrahydrofuran (20 mL) over 15 minutes at 25° C. Afterstirring for 3 hours at 25° C., the mixture is evaporated to an oil invacuo. To the residue is added ethyl ether and 1N citric acid, resultingin a precipitate. The ether phase is decanted from the mixture, and themixed precipitate and citric acid phases are washed exhaustively withethyl ether giving solution of the precipitates gum. The citric acidphase is layered with ethyl ether, and the pH of the citric acid phaseis adjusted to 5 with 6N NaOH. The product is extracted into a mixtureof ethyl ether and ethyl acetete, washed with brine, dried overanhydrous magnesium sulfate, and filtered. The filtrate is concentratedin vacuo and is purified by chromatography on 200 g silica gel elutedwith chloroform. The product (Compound 17) is obtained as a solid (2.39g, 63% yield). MS: APCI: M+1: 430.6 (M: 431.2). NMR spectrum isconsistent with structure.

[0604] Calcd. for C₂₇H₃₀N₂O₃, 0.075 CHCl₃: Theory: C 73.99, H 6.89, N6.37, Cl 1.81. Found: C 73.85, H 6.98, N 6.84, Cl 1.11.

EXAMPLE 18

[0605] Synthesis of6-((1S)-2-imidazolyl-1-phenylethoxy)-5-(prop-2-enyloxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 18)

[0606] 1.5-(Prop-2-enyloxymethyl)-6-hydroxy-2,3,4-trihydronaphthalen-1-one

[0607] To allyl alcohol (50 mL) is added5-chloromethyl-6-hydroxy-2,3,4-trihydronaphthalen-1-one (Chem. Pharm.Bull. 1977;25(11):2988-3002) (5.0 g, 23.7 mmol). To the mixture is addeddiisopropylamine (5.6 mL, 32 mmol) followed by stirring for 4 hours at70° C., then 25° C. for 18 hours. The excess allyl alcohol is evaporatedfrom the mixture under vacuum. The residue is taken up in a mixture ofethyl ether and 1N citric acid. The organic phase is washed with 1Ncitric acid, water, and brine. The organic phase is then separated,dried over anhydrous magnesium sulfate, and filtered. The filtrate isconcentrated in vacuo giving an oil which is purified by silica gelchromatography, eluted with ethyl acetate/hexane (25:75). The product isrecovered as a solid from hexane, dried in vacuo (2.19 g, 28% yield).NMR spectrum is consistent with structure. MS: APCI: M+1: 233.1 (M:232.3).

[0608] 2.6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(prop-2-enyloxymethyl)-2,3,4-trihydronaphthalen-1-one

[0609] (R)-2-Imidazol-1-yl-1-phenyl-ethanol (2.64 g, 17.7 mmol),triphenyl-phosphine (4.65 g, 17.7 mmol), and5-(prop-2-enyloxymethyl)-6-hydroxy-2,3,4-trihydronaphthalen-1-one (2.94g, 12.6 mmol) are suspended in dry tetrahydrofuran (25 mL). To thesuspension is added a solution of diethyl azodicarboxylate (2.97 g, 17.1mmol) in tetrahydrofuran (10 mL) over 25 minutes at 10° C. Afterstirring for 3 hours at 25° C., the mixture is evaporated to an oil invacuo. The residue is added to ethyl ether and 1N citric acid, resultingin a precipitate. The ether phase is decanted from the mixture, and themixed precipitate and citric acid phases are washed exhaustively withethyl ether. The citric acid phase is layered with ethyl ether, and thepH of the citric acid phase is adjusted to 5.5 with 6N NaOH. The productis extracted into ethyl ether, washed with 1N NaOH and brine, dried overanhydrous magnesium sulfate, and filtered. The filtrate is concentratedin vacuo and is purified by chromatography on 150 g silica gel elutedwith chloroform. The product (Compound 18) is obtained as a solid (4.07g, 80% yield). MS: APCI: M+1: 403.1 (M: 402.5). NMR spectrum isconsistent with structure.

[0610] Calcd. for C₂₅H₂₆N₂O₃, 0.2 CHCl₃: Theory: C 70.90, H 6.28, N6.55, Cl 4.98. Found: C 71.05, H 6.26, N 6.47, Cl 5.29.

EXAMPLE 19

[0611] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-methoxyethoxy)-methyl]-2,3,4-trihydronaphthalen-1-one(Compound 19)

[0612] 1.6-Hydroxy-5-(2-methoxyethoxymethyl)-2,3,4-trihydronaphthalen-1-one

[0613] To 2-methoxyethanol (50 mL) is added5-chloromethyl-6-hydroxy-2,3,4-trihydronaphthalen-1-one (Chem. Pharm.Bull. 1977;25(11):2988-3002) (5.0 g, 23.7 mmol). To the mixture is addeddiisopropylamine (4.42 mL, 25.3 mmol) followed by stirring for 4 hoursat 70° C. The excess 2-methoxyethanol is evaporated from the mixtureunder vacuum. The residue is taken up in a mixture of ethyl ether andwater. The organic phase is separated, washed with brine, dried overanhydrous magnesium sulfate, and filtered. The filtrate is concentratedin vacuo giving a solid that is purified by silica gel chromatography,eluted with ethyl acetate/hexane (25:75). The product is recovered as asolid from hexane, dried in vacuo (3.10 g, 52% yield). NMR spectrum isconsistent with structure. MS: APCI: M+1: 251.1 (M: 250.3).

[0614] 2.6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-methoxyethoxy)methyl]-2,3,4-trihydronaphthalen-1-one

[0615] (R)-2-Imidazol-1-yl-1-phenyl-ethanol (2.56 g, 13.6 mmol),triphenyl-phosphine (4.88 g, 18.6 mmol), and6-hydroxy-5-(2-methoxyethoxymethyl)-2,3,4-trihydronaphthalen-1-one (3.10g, 12.4 mmol) are suspended in dry tetrahydrofuran (25 mL). To thesuspension is added a solution of diethyl azodicarboxylate (3.24 g, 18.6mmol) in tetrahydrofuran (50 mL) over 45 minutes at 25° C. Afterstirring for 18 hours at 25° C., the mixture is evaporated to an oil invacuo. The residue is added to ethyl ether and 1N citric acid, resultingin a precipitate. The ether phase is decanted from the mixture, and themixed precipitate and citric acid phases are washed exhaustively withethyl ether. The citric acid phase is layered with ethyl ether, and thepH of the citric acid phase is adjusted to 13 with 6N NaOH. The productis extracted into a mixture of ethyl acetate and ethyl ether, washedwith brine, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate is concentrated in vacuo and is purified by chromatography on200 g silica gel eluted with chloroform. The product (Compound 19) isobtained as a solid (1.88 g, 36% yield). MS: APCI: M+1: 421.4 (M:420.5). NMR spectrum is consistent with structure.

[0616] Calcd. for C₂₅H₂₈N₂O₄, 0.23 CHCl₃, 0.275H₂O: Theory: C 66.91, H6.28, N 6.19, Cl 5.40, H₂O, 1.09. Found: C 67.05, H 6.35, N 6.13, Cl5.68, H₂O, 1.07.

EXAMPLE 19a

[0617]

[0618] Synthesis of6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-isobutoxymethyl-1-3,4-dihydro-2H-naphthalen-1-one(Compound 19a)

[0619] 1. Synthesis of6-Hydroxy-5-isobutoxymethyl-3,4-dihydro-2H-naphthalen-1-one

[0620] To a solution of5-Chloromethyl-6-hydroxy-3,4-dihydro-2H-naphthalen-lone, prepared asdescribed Chem. Pharm. Bull. 25(11)2988-3002(1077), (0.211 g, 0.001 mol)and triethylamine (0.167 ml, 0.0012 mol, Mallinckrodt) contained in a16×125 mm screw top glass tube, was added isobutyl alcohol (3 ml,Aldrich Chemical). The tube was capped with a teflon lined cap andplaced on an orbital mixing heat block at reflux temperature (˜108° C.)for 16 hrs. The reaction mixture was concentrated in vacuo to a pink-redsyrup. On addition of ethyl ether, a pinkish solid precipitated from thesyrup. Washed mixture with 5% citric acid, brine, and dried organicphase over anhydrous sodium sulfate. Evaporated mixture in vacuo toyield a red-pink powder, 0.210 g, 85% crude yield. Low resolution massspectroscopy (APCI) 249 [M+H]⁺.

[0621] 2.6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-isobutoxymethyl-3,4-dihydro-2H-naphthalen-1-one

[0622] To a solution of6-Hydroxy-5-isobutoxymethyl-3,4-dihydro-2H-naphthalen-1-one (0.21 g,0.85 mmol and freshly distilled tetrahydrofuran in an Ar(g) purgedflask, was added triphenylphosphine resin (0.823 g, loading 1.24 mmol/g,Argonaut Technologies) and (R)-2-Imidazol-1-yl-1-phenyl-ethanol (0.16 g,0.85 mmol). To this stirring mixture was added a solution of diethyldiazodicarboxylate (0.161 g, 1.02 mmol, Aldrich Chemical) in THF (1 ml).After stirring for 16 hrs. at 25° C. the resin was removed by filtrationand the mixture concentrated in vacuo to yield a yellow oil. The oil wasdissolved in methanol (10 ml) and Macroporous polystyrene sulfonic acidresin (1.13 g, loading 1.5 mmol/g, Argonaut Technologies) added. Afterstirring for 2 hrs. at 25° C., the resin was collected by gravityfiltration, washed with methanol (2×5 ml). Elution of product from theresin with 2.0 M ammonia in methanol (5 ml, Aldrich) and concentrationin vacuo yielded 120 mg yellow glass-like compound. High resolution massspectroscopy m/z (APCI) 419 [M+H]^(+.)

EXAMPLE 19b

[0623]

[0624] Synthesis of6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-propoxymethyl-3,4-dihydro-2H-naphthalen-1-one(Compound 19b)

[0625] 1. Synthesis of6-Hydroxy-5-propoxymethyl-3,4-dihydro-2H-naphthalen-1-one.

[0626] According to step 1 in the method of example 19a,5-Chloromethyl-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (0.211 g, 1.0mmol) was combined with triethylamine (0.167 ml, 1.2 mmol) inpropan-1-ol (3.0 ml, Aldrich Chemical) to produce 123 mg of desiredproduct as yellow crystals. Low resolution mass spectrum (APCI) m/z 235[M+H]⁺.

[0627] 2.6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-propoxymethyl-3,4-dihydro-2H-naphthalen-1-one

[0628] According to step 2 in the method of example 19a,6-Hydroxy-5-propoxymethyl-3,4-dihydro-2H-naphthalen-1-one (0.123 g, 0.53mmol), (R)-2-Imidazol-1-yl-1-phenyl-ethanol (0.131 g, 0.7 mmol),triphenylphosphine resin (0.620 g, loading 1.24 mmol/g, ArgonautTechnologies), diethyl diazodicarboxylate (0.121 ml, 0.77 mmol, AldrichChemical) and freshly distilled tetrahydrofuran (5 ml, Aldrich Chemical)were combined in a 2 dram screw topped vial with a teflon lined cap.After mixing on an inverting mixer at 25° C. for 16 hrs., the resin wasremoved by gravity filtration and mixture concentrated in vacuo to ayellow-brown syrup. The residue was dissolved in methanol (5 ml) andmacroporous polystyrene sulfonic acid resin (0.583 g, loading 1.5mmol/g, Argonaut Technologies) added. After mixing for 2 hrs. at 25° C.,the resin was collected by gravity filtration, washed with methanol (2×5ml). Elution of product from the resin with 2.0 M ammonia in methanol (5ml, Aldrich) and concentration in vacuo yielded 158 mg yellow glasscompound. Low resolution mass spectroscopy m/z (APCI) 405 [M+H]^(+.)

EXAMPLE 19c

[0629]

[0630] Synthesis of5-(1-Ethyl-propoxymethyl)-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one(Compound 19c)

[0631] 1. Synthesis of5-(1-Ethyl-propoxymethyl)-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one.

[0632] According to step (a) in the method of example 19a,5-Chloromethyl-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (0.211 g, 1.0mmol) was combined with triethylamine (0.167 ml, 1.2 mmol) inpentan-3-ol (3 ml, Aldrich Chemical) to produce 248 mg of desiredproduct as an orange-red oil. Low resolution mass spectrum (APCI) m/z263 [M+H]⁺.

[0633] 2.5-(1-Ethyl-propoxymethyl)-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one

[0634] According to step 2 in the method of example 19,5-(1-Ethyl-propoxymethyl)-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one(0.123 g, 0.53 mmol), (R)-2-Imidazol-1-yl-1-phenyl-ethanol (0.131 g, 0.7mmol), triphenylphosphine resin (0.620 g, loading 1.24 mmol/g, ArgonautTechnologies), diethyl diazodicarboxylate (0.121 ml, 0.77 mmol, AldrichChemical) and freshly distilled tetrahydrofuran (5 ml, Aldrich Chemical)were combined in a 2 dram screw topped vial with a teflon lined cap.After mixing on an inverting mixer at 25° C. for 16 hrs., the resin wasremoved by gravity filtration and mixture concentrated in vacuo to ayellow-brown syrup. The residue was dissolved in methanol (5 ml) andmacroporous polystyrene sulfonic acid resin (0.583 g, loading 1.5mmol/g, Argonaut Technologies) added. After mixing for 2 hrs. at 25° C.,the resin was collected by gravity filtration, washed with methanol (2×5ml). Elution of product from the resin with 2.0 M ammonia in methanol (5ml, Aldrich) and concentration in vacuo yielded 139 mg brown glasscompound. Low resolution mass spectroscopy m/z (APCI) 433 [M+H]^(+.)

EXAMPLE 19d

[0635]

[0636] Synthesis of(±)-5-sec-Butoxymethyl-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one(Compound 19d)

[0637] 1.(±)-5-sec-Butoxymethyl-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one.

[0638] According to step (a) in the method of example A,5-Chloromethyl-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (0.211 g, 1.0mmol) was combined with triethylamine (0.167 ml, 1.2 mmol) in(±)butan-2-ol (3 ml, Aldrich Chemical) to produce 159 mg of desiredproduct as an orange oil. Low resolution mass spectrum (APCI) m/z 249[M+H]⁺.

[0639] 2.(±)-5-sec-Butoxymethyl-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one

[0640] According to step (b) in the method of example A,(±)-5-sec-Butoxymethyl-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (0.159g, 0.64 mmol), (R)-2-Imidazol-1-yl-1-phenyl-ethanol (0.131 g, 0.7 mmol),triphenylphosphine resin (0.620 g, loading 1.24 mmol/g, ArgonautTechnologies), diethyl diazodicarboxylate (0.121 ml, 0.77 mmol, AldrichChemical) and freshly distilled tetrahydrofuran (5 ml, Aldrich Chemical)were combined in a 2 dram screw topped vial with a teflon lined cap.After mixing on an inverting mixer at 25° C. for 16 hrs., the resin wasremoved by gravity filtration and mixture concentrated in vacuo to ayellow-brown syrup. The residue was dissolved in methanol (5 ml) andmacroporous polystyrene sulfonic acid resin (0.583 g, loading 1.5mmol/g, Argonaut Technologies) added. After mixing for 2 hrs. at 25° C.,the resin was collected by gravity filtration, washed with methanol (2×5ml). Elution of product from the resin with 2.0 M ammonia in methanol (5ml, Aldrich) and concentration in vacuo yielded 139 mg dark brown glasscompound. Low resolution mass spectroscopy m/z (APCI) 419 [M+H]^(+.)

[0641]6-(2-Imidazol-1-yl-1-phenyl-ethoxy)-5-{[2-(pyridin-4-yloxy)-ethylamino]-methyl}-3,4-dihydro-2H-naphthalen-1-one

[0642] 2-(Pyridin-4-yloxy)-ethylamine (1.0 mL, 0.4 mmol, 0.4 M inα,α,α-trifluorotoluene) and6-((1S)-2-imidazoyl-1-phenylethoxy)-5-(bromomethyl)-2,3,4-trihydronapthalen-1-one(Example 65, step 1)(100 mg, 0.198 mmol) were sealed in a 16×120 mmscrew capped tube and heated to 50° C. (45 min). Reaction mixture wascooled to rt and partitioned between 2N sodium hydroxide and ethylacetate. The organic layer was separated, washed (brine), dried(Na₂SO₄), and concentrated in vacuo. The residue was purified by flashsilica gel chromatography (ethyl acetate/triethylamine/methanol, 17:2:1)to give 31 mg (32%) of the desired product as a colorless glass: (LC-MS,APCI) m/z 483 [M+H]⁺.

EXAMPLE 20

[0643] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-phenylethyl)-2,3,4-trihydronaphthalen-1-one(Compound 20)

[0644] 1. 6-Methoxy-5-phenylethynyl-2,3,4-trihydronapthalen-1-one

[0645] 5-Bromo-6-methoxy-2,3,4-trihydronapthalen-1-one (10.7 g, 0.04mol) (Z. Chem. 1970;10:70) and phenylacetylene (8.2 g, 0.08 mol) areadded to a mixture of dimethylformamide (80 mL) and triethylamine (40mL). The mixture is sparged with nitrogen gas, and copper iodide (228mg) is added. Dichlorobis-(triphenyl-phosphine)palladium (II) (1.12 g)and butylated hydroxytoluene (0.08 g) are added, and the resultingreaction mixture is heated to 108° C. for 2 hours. Another portion ofphenylacetylene (16 g, 0.16 mol) is slowly added over 3 hours followedby heating to 108° C. for 18 hours. The mixture is then evaporated invacuo, and the residue is taken up into ethyl ether. Insoluble materialis decanted. The organic phase is washed with 1N citric acid and thenbrine, dried over anhydrous magnesium sulfate, filtered and evaporatedin vacuo to a crude solid (32 g). The material is purified bychromatography on 400 g silica gel, eluted with a mixture of ethylacetate/hexane (10:90). The product is obtained as a solid (5.89 g, 53%yield). NMR spectrum is consistent with structure. MS: APCI: M+1, 277.2(M: 276.34).

[0646] 2. 6-Methoxy-5-phenethyl-2,3,4-trihydronapthalen-1-one

[0647] 6-Methoxy-5-phenylethynyl-2,3,4-trihydronapthalen-1-one (5.69 g,0.021 mol) and 5% palladium on barium sulfate (1.0 g) are added totetrahydrofuran (100 mL) followed by pressurization to 49 psi withhydrogen gas. At regular intervals, 3 additional 1 g portions of 5%palladium on barium sulfate are added over 36 hours during additionaltreatment with hydrogen gas at 49 psi. The mixture is then filtered andevaporated in vacuo to a solid (5.68 g, 98% yield). NMR spectrum isconsistent with structure. MS: APCI: M+1, 281.2 (M: 280.37).

[0648] 3. 6-Hydroxy-5-phenethyl-2,3,4-trihydronapthalen-1-one

[0649] 6-Methoxy-5-phenethyl-2,3,4-trihydronapthalen-1-one (5.39 g,0.192 mol) and sodium cyanide (4.71 g, 0.096 mol) are added todimethylsulfoxide (30 mL) and heated to 180° C. for 18 hours. Themixture is poured, while hot, into water (200 mL), washed with ethylether, and acidified to pH 1 with conc. HCl. The mixture is extractedwith ethyl ether, washed with brine, dried over anhydrous magnesiumsulfate, and filtered. The filtrate is concentrated in vacuo, giving asolid (2.87 g, 56% yield). NMR spectrum is consistent with structure.MS: APCI: M+1, 267.1 (M: 266.3)

[0650] 4.6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-phenylethyl)-2,3,4-trihydronaphthalen-1-one

[0651] To tetrahydrofuran (50 n-L) is added6-hydroxy-5-phenethyl-2,3,4-trihydronapthalen-1-one (2.67 g, 10 mmol),(R)-2-imidazol-1-yl-1-phenyl-ethanol (2.15 g, 11.4 mmol), andtriphenylphosphine (3.94 g, 15 mmol). A solution ofdiethylazodicarboxylate (2.61 g, 15 mmol) in tetrahydrofuran (25 ML) isadded over 1 hour with cooling to 5° C. After stirring for 18 hours at25° C., the mixture is evaporated in vacuo, and the residue is suspendedin ethyl ether and 1N citric acid, washed exhaustively with ethyl etherand the pH adjusted to 14 with 6N NaOH. The aqueous phase is extractedwith ethyl ether, which is subsequently separated, washed with brine,dried over anhydrous magnesium sulfate and filtered. The filtrate isevaporated to a solid (Compound 20) that is purified byrecrystallization and obtained as a solid (2.22 g, 51% yield). NMRspectrum is consistent with structure. MS: APCI: M+1, 437.3 (M: 436.6).

[0652] Calcd. for C₂₅H₂₈N₂O₂, 0.1 CHCl₃, 0.25H₂O: Theory: C 79.79, H6.46, N 6.36. Found: C 79.47, H 6.52, N 6.42.

EXAMPLE 21

[0653] Synthesis of5-(2H-Benzo[d]-1,3-dioxolan-5-yl)-6-((1S)-2-indazolyl-1-phenylethoxy)-2,3,4-trihydronaphthalen-1-one(Compound 21)

[0654] 1.5-(2H-Benzo[d]1,3-dioxolan-5-yl)-6-methoxy-2,3,4-trihydronaphthalen-1-one

[0655] Under nitrogen, a suspension of 0.35 g (0.3 mmol) oftetrakis(triphenyl-phosphine) palladium (0) in 25 mL dimethoxyethane istreated with 2.55 g (10 mmol), of5-bromo-6-methoxy-2,3,4-trihydronapthalen-1-one [Example 20, step 1] andstirred at room temperature for 10 minutes. To this is added a solutionof 2.5 g (15 mmol) of 3,4-methylenedioxyphenylboronic acid, and themixture is heated at reflux overnight. The reaction is then diluted withEtOAc and filtered through Celite. The filtrate is washed with sat.NaHCO₃ and sat. NaCl. Drying over MgSO₄ and removal of the solvent underreduced pressure gives the crude product. Chromatography on silica gel,eluting with CH₂Cl₂ gives 2.88 g (97.3% yield) of the product as a whitefoam. The structure is confirmed by NMR and mass spectroscopy.

[0656] 2.5-(2H-Benzo[d]1,3-dioxolan-5-yl)-6-hydroxy-2,3,4-trihydronaphthalen-1-one

[0657] A solution of 2.88 g (9.7 mmol) of the methoxy compound [Example21; step 1] in 15 mL DMSO is treated with 2.4 g (4.8.6 mmol) of crushedNaCN and heated at 180° C. overnight. The mixture is poured into H₂O,acidified with dil. HCl and extracted twice with EtOAc. The EtOAc iswashed with sat. NaCl, dried over MgSO₄, and the solvent removed underreduced pressure giving the crude product. This is taken up in Et₂Ocontaining a small amount of acetone and washed twice with 5% NaOH. TheNaOH solution is back washed with Et₂O and acidified with dil. HCl. Theproduct is extracted into EtOAc and the EtOAc washed with sat. NaCl.Drying over MgSO₄ and removal of the solvent under reduced pressureleaves 2.59 g of a dark oil. This is taken up in CHCl₃/MeOH (98:2) andpassed through a plug of silica gel. Removal of the solvent underreduced pressure leaves 1.94 g (70.8% yield) of the crude product, whichis used directly in the next reaction.

[0658] 3. 5-(2H-Benzo[d]1,3-dioxolan-5-yl)-6-((1S)-2-imidazolyl-1-phenylethoxy)-2,3,4-trihydronaphthalen-1-one

[0659] Under nitrogen, a solution of 1.94 g (6.9 mmol) of the phenol[Example 21; step 2] in 35 mL THF is treated with 1.42 g (7.6 mmol) of(R)-1-phenyl-2-(1-imidazoyl)ethanol and 2.16 g (8.2 mmol) oftriphenylphosphine. This is treated dropwise over 20 minutes with asolution of 1.3 mL (8.2 mmol) of diethyl azodicarboxylate in 10 mL THF.After stirring at room temperature for 4 days, the mixture is dilutedwith EtOAc, washed twice with H₂O, and then sat. NaHCO₃ followed by sat.NaCl. Drying over MgSO₄ and removal of the solvent under pressure givesthe crude product. Chromatography on silica gel, eluting withCH₂Cl₂/acetone (80:20) gives 1.55 g (50% yield) of the product (Compound21) as light tan foam. The structure is confirmed by NMR.

[0660] Calcd for C₂₈H₂₄N₂O₄.0.2CH₂Cl₂ (MW 469.77): Theory: C, 72.14 H,5.24 N, 5.97. Found: C, 71.94 H, 5.45 N, 6.17.

EXAMPLE 22

[0661] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(3-chlorophenyl)-2,3,4-trihydronaphthalen-1-one(Compound 22)

[0662] Following the procedure of Example 21, steps 1-3 but using 2.4 g(15 mmol) of 3-chlorophenylboronic acid, the crude product is obtained.Two chromatographies on silica gel, eluting with CH₂Cl₂/acetone (80:20)gives 0.95 g of the title product (Compound 22) as a cream foam. Thestructure is confirmed by NMR and mass spectroscopy.

[0663] Calcd for C₂₇H₂₃N₂O₂Cl.0.1CH₂Cl₂ (MW 451.42): Theory: C, 72.10 H,5.18 N, 6.21. Found: C, 72.15 H, 5.04 N, 6.11.

EXAMPLE 23

[0664] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-naphthyl)-2,3,4-trihydronaphthalen-1-one(Compound 23)

[0665] 1. 6-Methoxy-5-(2-naphthyl)-2,3,4-trihydronaphthalen-1-one

[0666] 5-Bromo-6-methoxy-2,3,4-trihydronapthalen-1-one (6.1 g, 0.024mol) and palladium tetrakis(triphenylphosphine) (0.7 g, 0.06 mmol) isadded to dimethoxyethane (40 mL). A suspension of 2-naphthylboronic acid(5.16 g, 0.03 mol) in absolute ethanol (20 mL) is added, followed byaddition of a solution of potassium carbonate (5.52 g, 0.04 mol) inwater (25 mL). The mixture is heated with vigorous stirring to 85° C.for 2.5 hours, followed by stirring at 25° C. for 18 hours. The mixtureis poured into ethyl acetate, filtered, and washed with 0.5M NaOH, 1Ncitric acid, and brine. The organic phase is stripped to an oil.Addition of ethyl ether induces crystallization. A solid is obtained(4.31 g, 71% yield). NMR spectrum is consistent with structure. MS:APCI: M+1, 303.1 (M: 302.4).

[0667] 2. 6-Hydroxy-5-(2-naphthyl)-2,3,4-trihydronaphthalen-1-one

[0668] 6-Methoxy-5-(2-naphthyl)-2,3,4-trihydronaphthalen-1-one (4.31 g,0.143 mol) and sodium cyanide (3.5 g, 0.071 mol) are added todimethylsulfoxide (25 mL) and heated to 180° C. for 18 hours. Themixture is poured while hot into water (200 mL) and acidified byaddition of conc. HCl to give a solid precipitate. The mixture isfiltered, and the damp solid is dissolved in ethyl acetate and washedwith brine. The solution is filtered, dried over anhydrous magnesiumsulfate, and evaporated to an oil. The material is purified by passingit through a short plug of silica gel as a dichloromethane solution,giving a crystalline solid by addition of ethyl ether (1.5 g, 36%yield). NMR spectrum is consistent with structure. MS: APCI: M+1, 289.1(M: 288.4).

[0669] 3.6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-naphthyl)-2,3,4-trihydronaphthalen-1-one

[0670] To tetrahydrofuran (25 mL) is added6-hydroxy-5-(2-naphthyl)-2,3,4-trihydronaphthalen-1-one (1.74 g, 5.1mmol), (R)-2-imidazol-1-yl-1-phenyl-ethanol (1.09 g, 5.8 mmol), andtriphenylphosphine (2.01 g, 7.6 mmol). A solution ofdiethylazodicarboxylate (1.33 g, 7.6 mmol) in tetrahydrofuran (10 mL) isadded over 30 minutes. After stirring for 3 hours at 25° C., the mixtureis evaporated in vacuo and the residue is suspended in ethyl ether and1N citric acid, washed exhaustively with ethyl ether, and the pHadjusted to 14 with 4N NaOH. The aqueous phase is extracted with ethylether which is separated, washed with brine, dried over anhydrousmagnesium sulfate, and filtered. The filtrate is evaporated to a solid(Compound 23) that is purified by recrystallization and obtained as asolid (1.03 g, 44% yield). NMR spectrum is consistent with structure.MS: APCI: M+1, 459.1 (M: 458.6).

[0671] Calcd. for C₃₁H₂₆N₂O₂: Theory: C 81.20, H 5.72, N 6.11. Found: C80.35, H 5.83, N 6.06.

EXAMPLE 24

[0672] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-(2-pyridyl)ethyl)-2,3,4-trihydronaphthalen-1-one(Compound 24)

[0673] 1.6-Methoxy-5-(2-pyridin-2-yl-ethenyl)-2,3,4-trihydronapthalen-1-one

[0674] A Pyrex glass pressure tube is charged with5-bromo-6-methoxy-2,3,4-trihydronapthalen-1-one (30 g, 0.12 mol),2-vinylpyridine (38 mL, 0.35 mol), sodium acetate (19.7 g, 0.24 mol),N,N-dimethylglycine (7.22 g, 0.07 mol), methanol (300 mL), andbis(benzonitrile)dichloropalladium (II) (2.8 g, 0.007 mol). The tube issealed and heated to 130° C. for 10 hours. After cooling, diethyletheris added, and the reaction mixture is filtered through a bed of celite.The organic layer is washed with saturated sodium bicarbonate solutionand then brine, dried over magnesium sulfate, and the solvent removed invacuo. The black residue is chromatographed using 20% ethyl acetate/80%hexanes to 50% ethyl acetate/50% hexanes. A tan solid (4 g) is obtained,which is recrystallized using hexane/ethyl acetate as the solvent (3.6g, 10.6% yield). MS: APCI 280.1 [M+1].

[0675] 2.6-Methoxy-5-(2-pyridin-2-yl-ethyl)-2,3,4-trihydronapthalen-1-one

[0676]6-Methoxy-5-(2-pyridin-2-yl-ethenyl)-2,3,4-trihydronapthalen-1-one (3.6g, 0.13 mol) in tetrahydrofuran (75 mL) is treated with 5% Pd/BaSO₄ (0.5g) in a Parr shaker under a Hydrogen atmosphere of 50 psi. After 10hours, there is no further uptake of hydrogen gas and the calculatedΔP=54.9#. The solvent is removed in vacuo. The residue is recrystallizedusing hexanes and ethyl acetate giving a light green solid (2.65 g, 73%yield). MS: APCI 282 [M+1].

[0677] 3.6-Hydroxy-5-(2-pyridin-2-yl-ethyl)-2,3,4-trihydronapthalen-1-one

[0678] 6-Methoxy-5-(2-pyridin-2-yl-ethyl)-2,3,4-trihydronapthalen-1-one(2.65 g, 0.0094 mol) is dissolved in DMSO (10 mL). Crushed sodiumcyanide (2.31 g, 0.047 mol) is added, and the reaction is heated to 180°C. for 3 hours. The reaction mixture is poured into water and cooled inan ice-water bath. Using a pH meter, the aqueous solution is acidifiedwith concentrated HCl to pH 5 and subsequently extracted with ethylacetate (3×). The organic solution is washed with brine, dried overMgSO₄, and the solvent removed in vacuo. A green solid is obtained (2.9g, 65% yield). MS: APCI 268.2 [M+1].

[0679] 4.6-((1S)-2-imidazolyl-1-phenylethoxy)-5-(2-(2-pyridyl)ethyl)-2,3,4-trihydronaphthalen-1-one

[0680] 6-Hydroxy-5-(2-pyridin-2-yl-ethyl)-2,3,4-trihydronapthalen-1-one(2.75 g, 0.0103 mol), (R)-2-imidazol-1-yl-1-phenyl-ethanol (2.08 g,0.012 mol), and triphenylphosphine (4.05 g, 0.015 mol) are dissolved indry THF (50 mL) under a nitrogen atmosphere and cooled in an ice-waterbath. DEAD reagent (2.36 mL, 0.015 mol) in dry THF (20 mL) is added over0.5 hour. The reaction mixture is stirred for an additional 2 hoursafter the DEAD reagent is added. Solvent is removed in vacuo. Theresidue is partioned between diethyl ether and 1N citric acid. Theaqueous solution is washed with diethyl ether several times. Then, theaqueous solution is made basic using 50% sodium hydroxide solution andextracted with ethyl acetate (3×). The organic layer is washed withbrine, dried over MgSO₄, and the solvent removed in vacuo. The residueis chromatographed using dichloromethane to 97% dichloromethane/3%methanol as eluent. A tan solid is obtained as the final product(Compound 24) (2.5 g, 56% yield) MS: APCI 438.1 [M+1].

[0681] Anal. Calcd. C₂₈H₂₇N₃O₂.0.16 mol DCM, MWC=451.14: Theory: C74.97, H 6.10, N 9.31. Found: C 74.97, H 6.34, N 9.06.

EXAMPLE 25

[0682] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[2-(1-oxy(2-pyridyl))ethyl]-2,3,4-trihydronaphthalen-1-one(Compound 25)

[0683] Compound 24 (0.4 g, 0.0015 mol) is dissolved in dichloromethane(10 mL) and cooled in an ice-water bath under N₂ atmosphere.Meta-chloroperbenzoic acid (0.42 g, 0.0024 mol) is added and thereaction is warmed to room temperature and stirred for 2 hours. Solventis removed in vacuo. Chromatography using DCM to DCM/MeOH 5% affords awhite foam (Compound 25) (0.24 g, 56% yield); MS: APCI 454.2 [M+1].

[0684] Anal. Calcd. C₂₈H₂₇N₃O₃.0.56 mol DCM, MWC=501.47: Theory: C68.41, H 5.66, N 8.38. Found: C 68.78, H 5.80, N 7.96.

EXAMPLE 26

[0685] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-(4-pyridyl)ethyl)-2,3,4-trihydronaphthalen-1-one(Compound 26)

[0686] The title compound (Compound 26) is obtained in a manner similarto Example 24, steps 1-4 using 4-vinylpyridine. MS: APCI 438.2 [M+1].

[0687] Anal. Calcd. C₂₈H₂₇N₃O₂.1.12H₂O/0.06 DCM, MWC=462.82: Theory: C72.82, H 6.39, N 9.08. Found: C 72.81, H 6.38, N 8.94.

EXAMPLE 26a

[0688]

[0689] Synthesis of(S)-6-(2-Imidazol-1-yl-1-phenylethoxy)-5-[2-(4-pyridyl-4-yl)ethyl]-3,4-dihydro-2H-naphthalen-1-one(Compound 26a)

[0690] The title compound was obtained in a manner similar to Example25, using(S)-6-(-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(2-pyridin-4-yl-ethyl)-3,4-dihydro-2H-naphthalen-1-one(Example 26). NMR (CDCl₃); MS APCI 454, [M+1]⁺; anal. calcd. C₂₈H₂₇N₃O₃0.24 EtOAc/1.73H₂O MWC=505.90, C, 68.76%; H, 6.45%; N, 8.31%, found C,68.81%; H, 6.48%; N, 8.30%

EXAMPLE 26b

[0691]

[0692] Synthesis of(S)-6-(-2-imidazol-1-yl-phenyl-ethoxy)-5-(2-pyridin-3-yl-ethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 26b)

[0693] The title compound was obtained in a manner similar to Example24, 1-4 using 3-vinylpyridine (Chirex). Obtained a white solid (1.15 g,91% yield). NMR MS APCI 438, [M+1]⁺; HPLC RT=13.87 min. 100% pure, 254nm; anal. calcd. for C₂₈H₂₇N₃O₂.2HCl/1.52H₂O, MWC=537.85, C, 62.53%; H,6.00%; N, 7.81% found C, 62.54%; H, 5.80%; N, 7.77%

EXAMPLE 26c

[0694]

[0695] Synthesis of(S)-6-(-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(2-pyridin-2-3-yl-ethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 26c)

[0696] 1. 4-vinylisoquinoline

[0697] 4-Bromoisoquinoline (10 g, 0.048 mol), Pd(OAc)₂ (1.07 g, 0.0048mol), (o-tol)₃P (2.95 g, 0.0096 mol), Et₃N (13.06 mL, 0.096 mol) and asaturated soln. of ethylene in MeCN (100 mL) were placed in a sealreaction apparatus and heated to 100° C. for 2 days. Solvent was removedin vacuo and EtOAc was added. Washed the organic layer with H₂O (2×),sat. NaHCO₃ (2×), and brine. The organic solution was dried over MgSO₄and the solvent was removed in vacuo. A brown oil (7.0 g) was obtainedand chromatographed using SiO₂, DCM/1% MeOH to DCM/2%MeOH giving ayellow oil (5.57 g, 75% yield). MS APCI (156), [M+H]⁺; anal. calcd. forC₁₁H₉N₁.0.07H₂O, MWC=156.46, C), 84.44%; H, 5.89%; N, 8.95% found C,84.48%; H, 5.84%; N, 8.66%.

[0698] 2.(S)-6-(-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(2-isoquinolin-4-yl-ethyl)-3,4-dihydro-2H-naphthalen-1-one

[0699] The title compound was obtained in a manner similar to Example24, 1-4 using 4-vinylisoquinoline. Obtained a brown solid (0.15 g, 89%yield). MS APCI 488 [M+H]⁺; anal. calcd. C₃₂H₂₉N₃O₂.2.57 HCl/2.39H₂OMWC=624.4, C, 61.56%; H, 5.87%; N, 6.73% found C, 61.16%; H, 5.90%; N,7.97%

EXAMPLE 27

[0700] Synthesis of Methyl4-(2-[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]ethyl}benzoate(Compound 27)

[0701] The title compound (Compound 27) is obtained in a manner similarto Example 24, steps 1-4 using 4-vinylbenzoic acid methyl ester. MS:APCI 495.1 [M+1].

[0702] Anal. Calcd. C₃₁H₃₀N₂O₄.0.3 mol EtOAc, MWC=525.4: Theory: C74.06, H 6.29, N 5.33. Found: C 74.04, H 6.27, N 5.33.

EXAMPLE 28

[0703] Synthesis of Methyl4-{2-[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]ethyl)benzoate(Compound 28)

[0704] Compound 27 (0.55 g, 0.0011 mol) is dissolved in THF (10 mL)/MeOH(10 mL) and 1N NaOH (4.4 mL) is added. The reaction mixture is stirredat room temperature over the weekend. Solvent is removed in vacuo. 1NHCl (4.4 mL) is added and extracted with EtOAc. The organic layer iswashed with brine, dried over MgSO₄, and the solvent removed in vacuo.Et₂O is added, triturating a white foam (Compound 28) (0.44 g, 83%yield); MS: APCI 481 [M+1].

[0705] Anal. Calcd. C₃₀H₂₈N₂O₂.0.52H₂O MWC=489.94: Theory: C 73.55, H5.97, N 5.72. Found C 73.55, H 5.91, N 5.52.

EXAMPLE 29

[0706] Synthesis of(4-{2-[2-((1S)-2-Imidazolyl-1-phenylethoxy)-5-oxo(6,7,8-trihydronaphthyl)]ethyl}phenyl)-N-methylcarboxamide(Compound 29)

[0707] Compound 28 (0.3 g, 0.63 mmol) is dissolved in dry THF (10 mL).Carbonyl diimidazole (0.11 g, 0.69 mmol) and 2M methylamine in THF (0.35mL, 0.69 mmol) are added. The reaction is refluxed overnight. Solvent isremoved in vacuo. Ethyl acetate is added, and the reaction mixture iswashed with sat. NaHCO₃ and brine, dried over MgSO₄, and the solventremoved in vacuo. Chromatography using DCM to DCM/MeOH 3% affords awhite foam (Compound 29) (0.13 g, 42% yield). MS: APCI 495.2 [M+1].

[0708] Anal. Calcd. C₃₁H₃₁N₃O₃.0.16 mol DCM/0.52 mol H₂O: Theory: C72.45, H 6.31, N 8.13. Found C 72.47, H 6.33, N 8.51.

EXAMPLE 30

[0709] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[2-(4-fluorophenyl)ethyl]-2,3,4-trihydronaphthalen-1-one(Compound 30)

[0710] The title compound (Compound 30) is obtained in a manner similarto Example 24, steps 1-4 using 4-fluorostyrene. A white solid isobtained (1.3 g, 38% yield), mp=106-108° C.; MS: APCI 455 [M+1].

[0711] Anal. Calcd. C₂₉H₂₇F₁N₂O₂:

[0712] Theory: C, 76.63; H, 5.99; N, 6.16.

[0713] Found: C, 76.53; H, 6.08; N, 6.08.

EXAMPLE 31

[0714] Synthesis of Methyl3-[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]propanoate(Compound 31)

[0715] 1. 5-[Ethylacrylate]-6-methoxy-1-tetralone

[0716] Ethyl acrylate (2.12 mL, 20 mmol) andbis(triphenylphosphine)-palladium (II) chloride (0.27 g, 0.39 mmol) areheated to reflux in triethylamine (5 mL) and N,N-dimethylformamide for 1hour. 6-Methoxy-5-bromo-1-tetralone (1.0 g, 3.9 mmol) is added to themixture and heated at reflux overnight. The reaction mixture is filteredthrough a bed of celite, washing with ethyl acetate. The organicsolution is washed with water (5×), sat. sodium bicarbonate solution andbrine. Subsequent drying over MgSO₄ and removal of the solvent in vacuoaffords crude product Chromatography using 25% EtOAc/hexanes affords ayellow solid (0.91 g, 85% yield). MS: APCI 275.1 [M+1].

[0717] 2. 5-[2-Ethyl-ethylcarboxylate]-6-methoxy-1-tetralone

[0718] The title compound is obtained in a manner similar to Example 24,step 2 using a Parr shaker to yield a yellow oil (2.32 g, 79% yield).MS: APCI 277.1 [M+1].

[0719] 3. 5-[2-ethylcarboxylic acid]-6-hydroxy-1-tetralone

[0720] The title compound is obtained in a manner similar to Example 24,step 3 using sodium cyanide in DMSO to yield a brown solid (1.64 g, 83%yield). MS: APCI 235.1 [M+1].

[0721] 4. 5-[2-Methyl-ethylcarboxylate]-1-6-hydroxy-1-tetralone

[0722] 5-[2-ethylcarboxylic acid]-6-hydroxy-1-tetralone (1.6 g, 6.8mmol) was dissolved in MeOH (10 mL)/toluene (10 mL) and cooled in anice-water bath. (Trimethylsilyl)diazomethane (3.4 mL, 6.8 mmol, 2.0Msolution in hexanes) was added dropwise and the mixture stirred for 18h. TLC and MS indicated incomplete reaction. Additional(trimethylsilyl)diazomethane (3.4 mL, 6.8 mmol, 2.0M soln in hexanes)was added and the mixture refluxed for 2 h. Acetic acid (1 mL) was addedand after 10 min all solvent removed in vacuo to afford a brown oilysolid (0.8 g, 47% yield). NMR (DMSO) was consistent with the product, MSAPCI 249 [M+H]+.

[0723] 5. Methyl3-[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]propanoate

[0724] The title compound (Compound 31) is obtained in a manner similarto Example 25, step 4 using5-5-[2-methyl-ethylcarboxylate]-6-hydroxy-1-tetralone to yield a yellowsolid (0.35 g, 26%). MS: APCI 419.6 [M+1].

[0725] Anal. Calcd. C₂₅H₂₆N₂O₄.0.11 DCM MWC=427.84: Theory: C 70.49, H6.18, N 6.55. Found: C 70.14, H 6.18, N 6.95.

EXAMPLE 32

[0726] Synthesis of3-[2-((1S)-2-Imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]propanoicacid (Compound 32)

[0727] The title compound (Compound 32) is obtained in a manner similarto Example 28 using compound 31 to yield a yellow solid (0.22 g, 88%yield). MS: APCI 405.1 [M+1].

[0728] Anal. Calcd. C₂₄H₂₄N₂O₄.EtOAc (0.1)/water (0.76) MWC=426.97:Theory: C 68.64, H 6.21, N 6.56. Found: C 68.63, H 6.43, N 6.70.

EXAMPLE 33

[0729] Synthesis of4-{[2-((1S)-2-Imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]methyl}benzenecarbonitrile(Compound 33)

[0730] 1.5-[(4-Bromophenyl)methyl]-6-methoxy-2,3,4-trihydronaphthalen-1-one

[0731] To cut zinc foil, 0.5 mm thick, (11.0 g, 0.16 mol) is addedtetrahydrofuran (15.0 mL) and 1,2-dibromoethane (0.300 mL) and themixture is heated twice to reflux with a hot air gun. After 5 minutes,the mixture is cooled to 0° C. A solution of p-bromobenzylbromide(15.7.0 g, 0.08 mol) in tetrahydrofuran (40 mL) is added dropwise to thezinc under nitrogen over 45 minutes. After 1 hour, the reaction isstopped, and the zinc reagent is used in the following reaction.

[0732] Palladium bis(dibenzylideneacetone) (0.58 g, 1 mol %) and1,1′-bis(diphenyl-phospino)ferrocene (0.55 g, 2 mol %) are dissolved intetrahydrofuran under nitrogen. After stirring for 10 minutes,5-bromo-6-methoxytetralone (12.8 g, 0.050 mol) is added at 0° C.followed by the zinc reagent (50 mL of 1.6 M solution, 0.08 mol). Thereaction is heated to 70° C. for 48 hours. The reaction is cooled andpoured into sat. NH₄Cl (500 mL) and extracted with ethyl acetate (2×100mL). The organic layers are washed with water (2×150 mL) and then brine(1×150 mL), dried over MgSO₄, filtered, and concentrated to give a darkbrown oil. Chromatography is carried out on silica gel, using 15% ethylacetate in hexane as eluent, to give a pale yellow solid (2.55 g, 18%yield). MS-APCI 292.0 [M+1].

[0733] 2. 4-[(2-Hydroxy-5-oxo-6,7,8-trihydronaphthyl)methyl]benzeneCarbonitrile

[0734] To a solution of the product from step 1 (1.75 g, 6 mmol) indimethylsulfoxide (25 mL) is added sodium cyanide (1.5 g, 30 mmol) andthe mixture is heated to 180° C. After 3 hours, the reaction mixture ispoured into ice-water (150 mL) and acidified to a pH of 1 withconcentrated hydrochloric acid. The aqueous solution is extracted withethyl ether (2×50 mL). The organic layers are combined, washed withbrine, dried over MgSO₄, filtered, and concentrated to give a tan solid.Recrystalization in 1:1 ethyl acetate/hexane gives a tan solid (0.60 g,36% yield). MS-APCI 278.2 [M+1].

[0735] 3.4-{[2-((1S)-2-Imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]methyl}benzenecarbonitrile

[0736] To a solution of the product of step 2 (0.50 g, 1.8 mmol) in drytetrahydrofuran (15 mL) is added (R)-2-imidazol-1-yl-1-phenyl ethanol(0.678 g, 3.6 mmol) and triphenylphosphine (0.932 g, 3.6 mmol). Thereaction mixture is cooled to 0° C. and treated with a solution ofdiethyl azodicarboxylate (0.600 mL, 4.0 mmol) in tetrahydrofuran (5 mL)dropwise. The reaction is warmed to room temperature and stirredovernight. The solution is concentrated, and the residue is taken up in50 mL ethyl acetate. The organic layer is washed with water (3×25 mL)and brine (2×25 mL). The solvent is removed in vacuo, and 25 mL of ethylether is added. The precipitate is filtered and the ether is removed.More ethyl ether is added, and the above procedure is repeated two moretimes. Fifty milliliters of ethyl acetate is added, and the solution isdried over MgSO₄, filtered, and concentrated to give a light tan foam.Chromatography is carried out on silica gel, using 1.0% methanol inmethylene chloride as eluent, to give a white foam as the final product(Compound 33) (0.207 g, 26% yield). MS-APCI 448.1 [M+1].

[0737] Analysis calculated for C₂₉H₂₅N₃O₂ 1.44H₂O. Theory: C 73.57, H5.94, N 8.87. Found: C 73.20, H 5.90, N 9.09.

EXAMPLE 34

[0738] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-bromo-2,3,4-trihydronaphthalen-1-one(Compound 34)

[0739] 1. 5-Bromo-6-hydroxy-2,3,4-trihydronapthalen-1-one

[0740] A solution of 2.09 g (8.2 mmol) of5-bromo-6-methoxy-2,3,4-trihydronapthalen-1-one (Z. Chem. 1970;10:70) in50 mL CH₂Cl₂ is cooled in an ice bath and treated dropwise rapidly with5.2 mL (55.6 mmol) of BBr₃. After stirring at 0° for 0.5 hour, thesolution is stirred at room temperature overnight. The solution ispoured into ice water and extracted twice with Et₂O. The Et₂O is washedtwice with 5% NaOH and the NaOH solution back extracted with Et₂O. TheNaOH solution is acidified with dil. HCl and extracted twice with Et₂O.The Et₂O is washed with sat. NaCl and dried over MgSO₄. Removal of theEt₂O under reduced pressure gives 1.52 g of the crude product. Twochromatographies on silica gel, eluting with CH₂Cl₂ gives 0.33 g (16.8%yield) of the product as a cream solid.

[0741] 2.6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-bromo-2,3,4-trihydronaphthalen-1-one

[0742] 5-Bromo-6-hydroxy-2,3,4-trihydronapthalen-1-one (6.96 g, 0.029mol), (R)-2-imidazol-1-yl-1-phenyl-ethanol (5.97 g, 0.032 mol) andtriphenylphosphine (11.43 g, 0.044 mol) are dissolved in dry THF (100mL) under a nitrogen atmosphere and cooled in an ice-water bath. DEADreagent (6.93 mL, 0.044 mol) in dry THF (20 mL) is added over 0.5 hour.The reaction mixture is stirred for an additional 2 hours after the DEADreagent is added. Solvent is removed in vacuo. The residue ispartitioned between diethyl ether and 1N citric acid. The aqueoussolution is washed with diethyl ether several times. Then, the aqueoussolution is made basic using 50% sodium hydroxide solution and extractedwith ethyl acetate (3×). The organic layer is washed with brine, driedover MgSO₄ and the solvent is removed in vacuo. The residue ischromatographed using dichloromethane to 97% dichloromethane/3% methanolas eluent. Obtained is a tan solid as the final product (Compound 34)(3.0 g, 25% yield) MS: APCI 412.1 [M+1].

[0743] Anal. Calcd. C₂₁H₁₉N₂Br₁O₂.0.06 mol DCM, MWC=416.40: Theory: C60.75, H 4.63, N 6.73. Found: C 60.36, H 4.42, N 7.22.

EXAMPLE 35

[0744] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(3-thienyl)-2,3,4-trihydronaphthalen-1-one(Compound 35)

[0745] Tetrakistriphenylphosphine palladium (0.083 g, 0.072 mmol) issuspended in dimethoxyethane (15 mL). Compound 34 (1.0 g, 2.4 mmol) isadded and stirred at room temperature for 10 minutes. 3-Thiopheneboronicacid (0.47 g, 3.6 mmol) in ethanol (10 mL) is added followed by 2 Msolution Na₂CO₃ (10 mL), and the reaction mixture is refluxed overnight.The reaction is filtered through a bed of celite, washing with EtOAc.The organic layer is washed with sat. NaHCO₃ solution and then brine,dried over MgSO₄ and the solvent removed in vacuo. Chromatography usingDCM to DCM/MeOH 3% affords a pink foam as the final product (Compound35) (0.78 g, 79% yield). MS: APCI 415.2 [M+1].

[0746] Anal. Calcd. C₂₅H₂₂N₂O₂S₁0.17 mol DCM, MWC=428.97: Theory: C70.48, H 5.25, N 6.53. Found: C 70.32, H 5.49, N 6.53.

EXAMPLE 36

[0747] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(3-furyl)-2,3,4-trihydronaphthalen-1-1-one,2,2,2-trifluoroacetic Acid (Compound 36)

[0748] The title compound (Compound 36) is obtained in a manner similarto Example 35, using 2-furanboronic acid. The reaction is purified byprep. HPLC using reverse phase 0-45% MeCN/water (TFA) and product islyophilyzed to give a white foam (0.06 g, 9% yield). MS: APCI 399 [M+1].

[0749] Anal. Calcd. C₂₅H₂₂N₂O₃.1.83 mol TFA/0.12 mol H₂O MWC=609.29:Theory: C 56.50, H 3.98, N 4.60. Found: C 56.49, H 3.99, N 4.41.

EXAMPLE 37

[0750] Synthesis of6-((1S)-2-Indazolyl-1-phenylethoxy)-5-amino-2,3,4-trihydronaphthalen-1-one(Compound 37)

[0751] 1.6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-nitro-2,3,4-trihydronaphthalen-1-one

[0752] To a solution of 6-hydroxy-5-nitro-1-tetralone (2.09 g, 10.1mmol) in dry THF (50 mL) is added (R)-2-imidazol-1-yl-1-phenyl-ethanol(2.28 g, 12.1 mmol) followed by triphenylphospine (3.18 g, 12.1 mmol).After approximately 10 minutes, diethylazodicarboxylate (1.9 mL, 12.1mmol) is added slowly. The reaction becomes homogenous within 2 minutes.The reaction is allowed to stir at room temperature (RT) overnight. Thereaction mixture is concentrated under reduced pressure, and the residueis triturated with Et₂O to remove some of the phospine by-products. Theresidue is dissolved in EtOAc and washed with H₂O, saturated aqueousNaHCO₃ and brine, dried over MgSO₄, and concentrated to give a foam/oil.Purification by chromatography (SiO₂, 10% to 20% acetone/CH₂Cl₂ then 5%MeOH/CH₂Cl₂) affords the title compound as a light brown foam (3.06 g,8.1 mmol, 80%). The structure is confirmed by NMR and mass spectrometry.MS: m/z 378 [M⁺+H].

[0753] 2.6-((1S)-24-Imidazolyl-1-phenylethoxy)-5-amino-2,3,4-trihydronaphthalen-1-one

[0754] A mixture of the product from step 1(2.05 g, 5.43 mmol), MeOH(135 mL), H₂O (30 mL) and glacial acetic acid (3.1 mL, 54 mmol) istreated at reflux with iron powder (3.01 g, 54 mmol). The reaction ismonitored by mass spectrometry and is complete in 5 hours. The volume ofsolvent is reduced under reduced pressure. EtOAc and dilute aqueousNaHCO₃ are added. A brownish-green emulsion forms which is filteredthrough Celite. The mixture is extracted with EtOAc. The combinedorganic layer is washed with dilute aqueous NaHCO₃ and brine, dried overNa₂SO₄, and concentrated under reduced pressure to give a brown solid.Purification by chromatography (EtOAc then 6% MeOH/CH₂Cl₂) gives theproduct (Compound 37) as a tan solid (1.43 g, 4.12 mmol, 76%). MS: m/z348 [M⁺+H].

EXAMPLE 37a

[0755]

[0756] Synthesis of5-Amino-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one(Compound 37a)

[0757] 1.5-Nitro-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one

[0758] To a solution of 6-hydroxy-5-nitro-1-tetralone (2.09 g, 10.1mmol) in dry THF (50 mL) was added (R)-2-imidazol-1-yl-1-phenyl-ethanol(2.28 g, 12.1 mmol) followed by triphenylphosphine (3.18 g, 12.1 mmol).After approximately 10 min, diethylazodicarboxylate (1.9 mL, 12.1 mmol)was added slowly. The reaction became homogenous within 2 min. Thereaction was allowed to stir at RT overnight. The reaction mixture wasconcentrated under reduced pressure and the residue was triturated withEt₂O to remove some of the phospine by-products. The residue wasdissolved in EtOAc and washed with H₂O, saturated aqueous NaHCO₃ andbrine, dried over MgSO₄, and concentrated to give a foam/oil.Purification by chromatography (SiO₂, 10 to 20% acetone/Cl₂Cl₂ then 5%MeOH/CH₂Cl₂) afforded the title compound as a light brown foam (3.06 g,8.1 mmol, 80%). The structure was confirmed by NMR and massspectrometry. MS m/z 378 (M⁺+H).

[0759] 2.5-Amino-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one

[0760] A mixture of5-nitro-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one(2.05 g, 5.43 mmol), MeOH (135 mL), H₂O (30 mL) and glacial acetic acid(3.1 mL, 54 mmol) was treated at reflux with iron powder (3.01 g, 54mmol). The reaction was monitored by mass spectrometry and was completein 5 h. The volume of solvent was reduced under reduced pressure. EtOAcand dilute aqueous NaHCO₃ were added. A brownish-green emulsion formedwhich was filtered through Celite. The mixture was extracted with EtOAc.The combined organic layer was washed with dilute aqueous NaHCO₃ andbrine, dried over Na₂SO₄, and concentrated under reduced pressure togive a brown solid. Purification by chromatography (EtOAc then 6%MeOH/CH₂Cl₂) gave the product as a tan solid (1.43 g, 4.12 mmol, 76%).The structure was confirmed by NMR and mass spectrometry. MS m/z 348(M⁺+H).

EXAMPLE 38

[0761]

[0762] Synthesis ofN-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-benzenesulfonamide(Compound 38)

[0763] To a solution of5-amino-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one(100 mg, 0.288 mmol) in CH₂Cl₂ (2 mL) was added pyridine (47 mL, 0.576mmol, 2 equiv) followed by benzenesulfonyl chloride (44 μL, 0.345 mmol,1.2 equiv). The reaction was allowed to stir overnight at RT. Thereaction was diluted with CH₂Cl₂, washed with saturated aqueous NH₄Cland brine, dried over MgSO₄ to give an oil. Purification bychromatography (4% MeOH/CH₂Cl₂) gave the title compound as a white foam(114 mg, 0.234 mmol, 81%). The structure was confirmed by NMR and massspectrometry. MS m/z 488 (M⁺+H).

EXAMPLE 39

[0764]

[0765] Synthesis ofN-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-1-phenyl-methanesulfonamide(Compound 39)

[0766] The procedure in Example 38 was followed, exceptα-toluenesulfonyl chloride (83 mg, 0.432 mmol, 1.5 equiv) was used.After stirring overnight, the reaction was diluted with CH₂Cl₂ and 1NHCl was added. The mixture was extracted with CH₂Cl₂. The organic layerwas washed with brine, dried over MgSO₄, and concentrated to give afoam. Purification by chromatography (5% MeOH/CH₂Cl₂ with 1% NH₄OH)afforded the title compound as an off-white foam (108 mg, 0.215 mmol,75%). The structure was confirmed by NMR and mass spectrometry. MS m/z502 (M⁺+H).

EXAMPLE 39a

[0767]

[0768] Synthesis ofN-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-2-pyridin-2-yl-acetamide(Compound 39a)

[0769] To a solution of5-amino-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one(100 mg, 0.288 mmol) and 2-pyridylacetic acid HCl (67 mg, 0.386 mmol) inDMF (3 mL) was added EDCI HCl (111 mg, 0.576 mmol, 2 equiv). The yellowsolution turned orange overnight. Some of the DMF was removed underreduced pressure. The residue was dissolved in H₂O and 1 M NaOH wasadded until the solution was basic (pH 10). The mixture was extractedthoroughly with CH₂Cl₂. The organic layer was washed with brine, driedover Na₂SO₄ and concentrated to give a bright yellow oil. Purificationby chromatography (7% MeOH/CH₂Cl₂) afforded the title compound as a paleyellow foam (107 mg, 0.229 mmol, 80%). The structure was confirmed byNMR and mass spectrometry. MS m/z 467 (M⁺+H).

EXAMPLE 40

[0770]

[0771] Synthesis of Pyridine-2-carboxylic Acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide(Compound 40)

[0772] To a solution of5-amino-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one(150 mg, 0.432 mmol), picolinic acid (64 mg, 0.518 mmol) and HOBT (73mg, 0.540 mmol) in DMF (4 mL) was added N-methylmorpholine (62 μL, 0.562mmol) followed by EDCI HCl (108 mg, 0.562 mmol). After 2 days, the DMFwas removed under reduced pressure. The residue was partitioned betweenEtOAc and H₂O. The organic layer was washed with H₂O and brine, driedover Na₂SO₄ and concentrated to give a brown oil. Purification bychromatography (3-5% MeOH/CH₂Cl₂) afforded the title compound as a tanfoam (160 mg, 0.354 mmol, 82%). The structure was confirmed by NMR andmass spectrometry. MS m/z 453 (M⁺+H).

EXAMPLE 40a

[0773]

[0774] Synthesis of Isoquinoline-1-carboxylic Acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide(Compound 40a)

[0775] The procedure in Example 40 was followed using1-isoquinolinecarboxylic acid. Purification by chromatography (5%MeOH/CH₂Cl₂) afforded the title compound as a white foam (135 mg, 0.269mmol, 93%). The structure was confirmed by NMR and mass spectrometry. MSm/z 503 (M⁺+H).

EXAMPLE 40b

[0776]

[0777] Synthesis of Isoquinioline-3-carboxylic acid[2-((S)-2-imidazol-1-yl-1-phenylethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide(Compound 40b)

[0778] The procedure in Example 40 was followed using3-isoquinolinecarboxylic acid hydrate. Purification by chromatography(5% MeOH/CH₂Cl₂) afforded the title compound as a tan foam (63 mg, 0.125mmol, 44%). The structure was confirmed by NMR and mass spectrometry. MSm/z 503 (M⁺+H).

EXAMPLE 40c

[0779]

[0780] Synthesis of Pyrazine-2-carboxylic acid[2-((S)-2-imidazol-1-yl-4-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide(Compound 40c)

[0781] To a mixture of5-amino-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one(100 mg, 0.288 mmol), 2-pyrazinecarboxylic acid (43 mg, 0.346 mmol), andHATU (132 mg, 0.346 mmol) was added CH₂Cl₂ (2.5 mL) and Et₃N (48 μL,0.346 mmol). The suspension became homogenous after 1 h. The reactionwas stirred overnight at RT. The mixture was diluted with CH₂Cl₂ andwashed with H₂O, saturated aqueous NaHCO₃ and brine, dried over Na₂SO₄,and concentrated to give a foam/oil. Purification by chromatography(SiO₂, 6% MeOH/CH₂Cl₂ with 1% NH₄OH) afforded the title compound as afoam (120 mg, 0.265 mmol, 92%). The structure was confirmed by NMR andmass spectrometry. MS m/z 454 (M⁺+H).

EXAMPLE 40d

[0782]

[0783] Synthesis of 5-(4-Chloro-phenyl)-oxazole-4-carboxylic acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide(Compound 40d)

[0784] The procedure in Example 40c was followed using5-(4-chloro-phenyl)-oxazole-4-carboxylic acid. Purification bychromatography (SiO₂, 60% EtOAc/CH₂Cl₂ then 5% MeOH/CH₂Cl₂) afforded thetitle compound as a foam (120 mg, 0.217 mmol, 75%). The structure wasconfirmed by NMR and mass spectrometry. MS m/z 553 (M⁺+H).

EXAMPLE 40e

[0785]

[0786] Synthesis ofN-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-4-yl]-2-chloro-nicotinamide(Compound 40e)

[0787] The procedure in Example 40c was followed using 2-chloronicotinicacid. The reaction was heated to reflux (40° C.) for 2 days.Purification by chromatography (SiO₂, 2-5% MeOH/CH₂Cl₂) afforded thetitle compound as a foam (10 mg, 0.021 mmol, 7%). The structure wasconfirmed by NMR and mass spectrometry. MS m/z 487 (M⁺+H).

EXAMPLE 40f

[0788]

[0789] Synthesis ofN-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-4-1-yl]-2-phenoxy-nicotinamide(Compound 40f)

[0790] The procedure in Example 40c was followed using2-phenoxynicotinic acid.

[0791] The reaction was heated to reflux (40° C.) for 2 days.Purification by chromatography (SiO₂, 2-5% MeOH/CH₂Cl₂) afforded thetitle compound as a foam (140 mg, 0.257 mmol, 89%). The structure wasconfirmed by NMR and mass spectrometry. MS m/z 545 (M⁺+H).

EXAMPLE 40g

[0792]

[0793] Synthesis of Quinoline-8-carboxylic Acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide(Compound 40g)

[0794] The procedure in Example 40c was followed using2-phenoxynicotinic acid. The reaction was heated to reflux (40° C.) for1 day. Purification by chromatography (SiO₂, 2-5% MeOH/CH₂Cl₂) affordedthe title compound as a foam (135 mg, 0.269 mmol, 93%). The structurewas confirmed by NMR and mass spectrometry. MS m/z 503 (M⁺+H).

EXAMPLE 41

[0795]

[0796] Synthesis of[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl-carbamicAcid Tert-Butyl Ester (Compound 41)

[0797] 1.2-Chloro-N-(2-hydroxy-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl)acetamide.

[0798] 6-Hydroxytetralone (4.87 g, 30.0 mmol) was added to a mixture ofglacial acetic acid (20 mL) and concentrated H₂SO₄ (20 mL) cooled to 0°C. N-Hydroxymethyl-2-chloroacetamide (3.71 g, 30.0 mmol) was added andthe mixture was allowed to warm to RT. After stirring overnight, thereaction was poured into ice. An orange sludge formed and the mixturewas extracted thoroughly with EtOAc. The organic layer was washed withH₂O and brine, dried over MgSO₄ and concentrated to give an orange foam(5.6 g). Recrystalization (EtOH/H₂O) afforded the title compound asorange needles (2.46 g, 9.2 mmol, 31%). MS m/z 268/270 (M⁺+H).

[0799] 2.(2-Hydroxy-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl)-carbamic AcidTert-Butyl Ester.

[0800] To a slurry of2-Chloro-N-(2-hydroxy-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl)-acetamide(1.85 g, 6.92 mmol) in THF (25 mL) was added di-tert-butyl dicarbonate(6.04 g, 27.7 mmol, 4 equiv) followed by dimethylaminopyridine (338 mg,2.77 mmol, 0.4 equiv). The reaction became homogenous and turned red.The reaction was stirred at RT for 2 days at which time it was an orangeslurry. The reaction was concentrated and chromatographed (20-30%EtOAc/Hexanes) to give the bis-Boc chloroacetamide as a white foam (2.19g, 4.69 mmol, 68%). MS m/z 468/470 (M⁺+H).

[0801] To a solution of the bis-Boc compound (2.19 g) in THF (30 mL) andMeOH (10 mL) was added 2 N LiOH (10 mL). The mixture was stirredovernight at RT. Some of the solvent was removed under reduced pressure.The residue was neutralized with 1 N HCl and extracted with CH₂Cl₂several times. The organic layer was washed with brine, dried over MgSO₄and concentrated to give a mixture of the mono- and bis-Boc amines. Thismixture was treated with Mg(ClO₄)₂ in CH₃CN (30 mL) at 50° C. for 4 h.The solvent was removed under reduced pressure and the residue wasdissolved in EtOAc. The organics were washed with dilute HCl and brine,dried over Na₂SO₄ and concentrated under reduced pressure to give awhite solid. Purification by chromatography (30-40% EtOAc/Hexanes) gavethe title compound as a white solid (0.964 g, 3.31 mmol, 71%). MS m/z292 (M⁺+H).

[0802] 3.[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-carbamicAcid Tert-Butyl Ester

[0803] A round bottom flask was charged with(2-Hydroxy-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl)-carbamic acidtert-butyl ester (700 mg, 2.40 mmol),(R)-2-imidazol-1-yl-1-phenyl-ethanol (544 mg, 2.89 mmol),triphenylphospine (759 mg, 2.89 mmol) and dry THF (14 mL). Afterapproximately 15 nm, diethylazodicarboxylate (0.46 mL, 2.89 mmol) wasadded slowly. The reaction was stirred overnight and concentrated togive a yellow oil. Purification by chromatography (10-20% acetone/CH₂Cl₂then 5% MeOH/CH₂Cl₂) afforded the title compound as a white foam (0.850g, 1.84 mmol, 77%). The structure was confirmed by NMR and massspectrometry. MS m/z 462 (M⁺+H).

EXAMPLE 42

[0804]

[0805] Synthesis ofN-[2-((S)-2-Imidazol-1-y-1-phenyl-71-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-benzenesulfonamide(Compound 42)

[0806] 1.5-Aminomethyl-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-oneBis-Hydrochloride

[0807][2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-carbamicacid tert-butyl ester (0.830 g, 1.80 mmol) was dissolved in dioxane (10mL) and 4M HCl in dioxane (4 mL) was added. After 15 minutes, a whiteprecipitate formed. The precipitate was collected by filtration, washedwith Et₂O and dried in a vacuum oven to give the title compound as awhite fluffy solid (0.761 g, 1.75 mmol, 97%). The structure wasconfirmed by NMR, mass spectrometry and elemental analysis. MS m/z 362(M+H).

[0808] 2.N-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-benzenesulfonamide

[0809]5-Aminomethyl-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-onebis-hydrochloride (74 mg, 0.171 mmol) was dissolved in pyridine (1 mL)and catalytic DMAP (2 mg) was added followed by benzenesulfonyl chloride(26 μL, 0.205 mmol, 1.2 equiv). The reaction was stirred overnight atRT. The mixture was concentrated and the residue was dissolved inCH₂Cl₂. The organics were washed with H₂O and brine, dried over MgSO₄and concentrated to give a tan foam. Purification by chromatography (5%MeOH/EtOAc with 1% NH₄OH) afforded the title compound as a white foam(57 mg, 0.114 mmol, 67%). The structure was confirmed by NMR and massspectrometry. MS m/z 502 (M⁺+H).

EXAMPLE 42a

[0810]

[0811] Synthesis ofN-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-4-methoxy-benzenesulfonamide(Compound 42a)

[0812] To a solution of5-aminomethyl-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-onebis-hydrochloride (40 mg, 0.092 mmole) in CH₂Cl₂ (1 mL) and pyridine (1mL) was added 4-methoxybenzenesulfonyl chloride (0.75 mL, 0.4 M solutionin trifluorotoluene, 3 equiv). The reaction was shaken overnight. Apolyamine resin was added to quench the excess sulfonyl chloride. Themixture was filtered and concentrated. The residue was dissolved inEtOAc and washed with 1 M NaOH and brine, dried over Na₂SO₄ andconcentrated to give a light brown oil. Purification by chromatography(5% MeOH/CH₂Cl₂ with 1% NH₄OH) gave the title compound as an off-whitefoam (32 mg, 0.060 mmol, 66%). The structure was confirmed by NMR andmass spectrometry. MS m/z 532 (M⁺+H).

EXAMPLE 42b

[0813]

[0814] Synthesis of2,4-Difluoro-N-[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-benzenesulfonamide;Compound with Trifluoro-Acetic Acid (Compound 42b)

[0815] The procedure in Example 42a was followed using2,4-difluorobenzenesulfonyl chloride. Purification by HPLC (10-100%CH₃CN/H₂O with 0.05% TFA) afforded the title compound as the TFA salt(46 mg, 0.071 mmol). The structure was confirmed by NMR and massspectrometry. MS m/z 538 (M⁺+H).

EXAMPLE 42c

[0816]

[0817] Synthesis of2-{[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-sulfonyl}-benzoicAcid Methyl Ester; Compound with Trifluoro-Acetic Acid (Compound 42c)

[0818] The procedure in Example 42a was followed using2-carbomethoxybenzenesulfonyl chloride. Purification by HPLC (10-100%CH₃CN/H₂O with 0.05% TFA) afforded the title compound as the TFA salt(27 mg, 0.040 mmol). The structure was confirmed by NMR and massspectrometry. MS m/z 560 (M⁺+H).

EXAMPLE 42d

[0819]

[0820] Synthesis of 2,5-Dichloro-thiophene-3-sulfonic Acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-amide;compound with Trifluoro-Acetic Acid (Compound 42d)

[0821] The procedure in Example 42a was followed using2,5-dichloro-thiophene-3-sulfonyl chloride. Purification by HPLC(10-100% CH₃CN/H₂O with 0.05% TFA) afforded the title compound as theTFA salt (54 mg, 0.078 mmol). The structure was confirmed by NMR andmass spectrometry. MS m/z 577 (M⁺+H).

EXAMPLE 42e

[0822]

[0823] Synthesis of3-Chloro-N-[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-benzenesulfonamide;Compound with Trifluoro-Acetic Acid (Compound 42e)

[0824] The procedure in Example 42a was followed using3-chlorobenzenesulfonyl chloride. Purification by HPLC (10-100%CH₃CN/H₂O with 0.05% TFA) afforded the title compound as the TFA salt(48 mg, 0.074 mmol). The structure was confirmed by NMR and massspectrometry. MS m/z 536 (M⁺+H).

EXAMPLE 42f

[0825]

[0826] Synthesis of Naphthalene-2-sulfonic Acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-amide;Compound with Trifluoro-Acetic Acid (Compound 42f)

[0827] The procedure in Example 42a was followed using2-naphthalenesulfonyl chloride. Purification by HPLC (10-100% CH₃CN/H₂Owith 0.05% TFA) afforded the title compound as the TFA salt (10 mg,0.015 mmol). The structure was confirmed by NMR and mass spectrometry.MS m/z 552 (M⁺+H).

EXAMPLE 42g

[0828]

[0829] Synthesis ofN-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-4-ylmethyl]-C-phenyl-methanesulfonamide(Compound 42g)

[0830] The procedure in Example 42a was followed using α-toluenesulfonylchloride. Purification by chromatography (3% MeOH/CH₂Cl₂ with 1% NH₄OH)afforded the title compound (20 mg, 0.039 mmol). The structure wasconfirmed by NMR and mass spectrometry. MS m/z 516 (M⁺+H).

EXAMPLE 42h

[0831]

[0832] Synthesis of Pyridine-2-carboxylic Acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-amide(Compound 42h)

[0833] To a solution of5-aminomethyl-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-onebis-hydrochloride (69 mg, 0.159 mmol), picolinic acid (24 mg, 0.191mmol) and HOBT (27 mg, 0.199 mmol) in DMF (1.6 mL) was addedN-methylmorpholine (56 μL, 0.51 mmol) followed by EDCI (40 mg, 0.207mmol).

[0834] The reaction was stirred for 7 h at RT. The reaction was pouredinto dilute aqueous NaHCO₃ and the mixture was extracted with EtOAc. Theorganic layer was washed with brine, dried over Na₂SO₄ and concentrated.Purification by chromatography (5% MeOH/CH₂Cl₂) gave the title compoundas a white foam (53 mg, 0.114 mmol, 71%). The structure was confirmed byNMR and mass spectrometry. MS m/z 467 (M⁺+H).

EXAMPLE 42i

[0835]

[0836] Synthesis ofN-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-4-ylmethyl]-benzamide(Compound 42i)

[0837] The procedure in Example 42h was followed using benzoic acid.Purification by chromatography (5% MeOH/CH₂Cl₂) gave the title compoundas a tan foam (137 mg, 0.295 mmol). The structure was confirmed by NMRand mass spectrometry. MS m/z 466 (M⁺+H).

EXAMPLE 42j

[0838]

[0839] Synthesis of((S)-1-{[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-napthalen-ylmethyl]-carbamoyl}-3-methylsulfanyl-propyl)-carbamicAcid Tert-Butyl Ester (Compound 42j)

[0840] The procedure in Example 42h was followed usingN-Boc-L-Methionine. Purification by chromatography (5% MeOH/CH₂Cl₂) gavethe title compound as a white foam (183 mg, 0.309 mmol, 67%). Thestructure was confirmed by NMR and mass spectrometry. MS m/z 593 (M⁺+H).

EXAMPLE 42k

[0841]

[0842] Synthesis of(S)-2-Amino-N-[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-4-methylsulfanyl-butyramide(Compound 42k)

[0843] To a solution of((S)-1-{[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-carbamoyl}-3-methylsulfanyl-propyl)-carbamicacid tert-butyl ester (153 mg, 0.258 mmol) in MeOH (1 mL) was added 4 MHCl in dioxane (3 mL). The mixture was concentrated after 3 h. Theresidue was neutralized with aqueous NaHCO₃ and the mixture wasextracted with EtOAc. The organic layer was washed with brine, driedover Na₂SO₄ and concentrated to give a pale yellow oil. Purification bychromatography (5% MeOH/CH₂Cl₂ with 1% NH₄OH) afforded the titlecompound as a white foam (76 mg, 0.154 mmol, 60%).

[0844] The structure was confirmed by NMR and mass spectrometry. MS m/z493 (M⁺+H).

EXAMPLE 43

[0845]

[0846] Synthesis of2-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-isoindole-1,3-dione(Compound 43)

[0847] 1.2-(2-Hydroxy-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl)-isoindole-1,3-dione.

[0848] To a solution of 6-hydroxy-1-tetralone (4.87 g, 30.0 mmol) inconcentrated H₂SO₄ (50 mL) was added N-(hydroxymethyl)phthalimide (5.32g, 30.0 mmol) at RT. The reaction was exothermic. The mixture wasstirred overnight and poured into ice. A precipitate formed and themixture was filtered to give a brown solid. Several recrystalizations(EtOH and EtOAc) were attempted and 1.38 g of the title compound wasobtained. The structure was confirmed by NMR and mass spectrometry. MSm/z 322 (M⁺+H).

[0849] 2.2-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-isoindole-1,3-dione

[0850] To a slurry of2-(2-Hydroxy-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl)-isoindole-1,3-dione(862 mg, 2.68 mmol) in THF (17 mL) was added®-2-imidazol-1-yl-1-phenyl-ethanol (606 mg, 3.22 mmol) andtriphenylphospine (846 mg, 3.22 mmol). After 15 min,diethylazodicarboxylate (0.51 mL, 3.22 mmol) was added and the reactionbecame homogenous. The reaction was stirred for 2 days and concentratedto give a reddish-brown foam. Purification by chromatography (10-20%acetone/CH₂Cl₂ then 5% MeOH/CH₂Cl₂) afforded the title compound as alight brown foam (1.15 g, 2.35 mmol, 87%). The structure was confirmedby NMR and mass spectrometry. MS m/z 492 (M⁺+H).

EXAMPLE 44

[0851] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-phenylpropyl)-2,3,4-trihydronaphthalen-1-one(Compound 44)

[0852] 1.3-(4,4-Dimethyl(1,3-oxazolin-2-yl))-1-methoxy-2-(2-phenylpropyl) Benzene

[0853] Under nitrogen, a solution of 12.0 g (0.051 mol) of2-(2,3-dimethoxyphenyl)-4,4-dimethyl-2-oxazoline (J. Org. Chem.1978;43:1372) in 100 mL THF is treated dropwise with a Grignard solutionprepared from 13.2 g (0.066 mol) of 1-bromo-2-phenylpropane and 1.6 g(0.066 g-atom) of magnesium in 50 mL THF. After the addition iscomplete, the solution is stirred at room temperature overnight.Saturated NH₄Cl solution is added and the mixture extracted twice withEt₂O. The Et₂O is washed with sat. NaCl, dried over MgSO₄, and thesolvent removed under reduced pressure leaving the crude product.Chromatography on silica gel, eluting with CHCl₃, gives 9.86 g of impureproduct. This is taken up in Et₂O and washed with 5% NaOH solution, thensat. NaCl. Drying over MgSO₄ and removal of the solvent under reducedpressure leaves 8.0 g (48.5% yield) of the pure product. The structureis confirmed by NMR and mass spectroscopy.

[0854] 2. 3-Methoxy-2-(2-phenylpropyl)benzoic Acid

[0855] A mixture of 8.0 g (24.7 mmol) of the oxazoline in 500 mL of 18%HCl is heated at reflux for 3 days. The slightly hazy solution isextracted with Et₂O and the Et₂O washed with 5% NaOH. The NaOH solutionis washed with Et₂O and acidified to the Congo red end point with conc.HCl. The mixture is extracted with Et₂O and the Et₂O washed with sat.NaCl. Drying over MgSO₄ and removal of the solvent under reducedpressure gives 5.92 g (88.6% yield) of the product as an oil. Thestructure is confirmed by NMR and mass spectroscopy.

[0856] 3. [3-Methoxy-2-(2-phenylpropyl)phenyl]methan-1-ol

[0857] To a suspension of 1.7 g (43.8 mmol) of LAH in 50 mL THF is addeddropwise a solution of 5.92 g (21.9 mmol) of the acid of step 2 in 50 mLTHF. After stirring at room temperature for 0.5 hour, the solution isheated at reflux overnight. The mixture is decomposed with 1N H₂SO₄ andextracted with EtOAc. The EtOAc is washed with 1N H₂SO₄, H₂O, sat.NaHCO₃, and sat. NaCl. Drying over MgSO₄ and removal of the solventunder reduced pressure left 5.11 g (91% yield) of the product as an oil.The structure is confirmed by NMR and mass spectroscopy.

[0858] 4. 3-(Chloromethyl)-1-methoxy-2-(2-phenylpropyl)benzene

[0859] A solution of 5.11 g (19.9 mmol) of the alcohol of step 3 in 50mL CH₂Cl₂ is treated with 5.9 g (29.9 mmol) of BaCO₃ and cooled in ice.This is then treated dropwise with 2.2 mL (29.9 mmol) of SOCl₂. Afterstirring at 0° for 15 minutes, the mixture is stirred at roomtemperature overnight. The mixture is diluted with CH₂Cl₂, filtered,washed with sat. NaHCO₃, and then with sat. NaCl. Drying over MgSO₄ andremoval of the solvent under reduced pressure leaves 4.85 g (88.7%yield) of the product as an oil. The structure is confirmed by NMR andmass spectroscopy.

[0860] 5. Ethyl (2Z)-3-[3-methoxy-2-(2-phenylpropyl)phenyl]prop-2-enoate

[0861] Under nitrogen, a solution of 4.85 g (17.7 mmol) of thechloromethyl compound of step 4, 8.5 mL (35.3 mmol) of tributylamine,and 2.9 mL (26.5 mmol) of ethyl acrylate is treated with 80 mg (0.4mmol) of Pd(Oac)₂ and heated at 100° C. overnight. An additional 2.0 mLof ethyl acrylate and 80 mg Pd(Oac)₂ is added and the mixture heated at100° C. for an additional night. The mixture is diluted with Et₂O andwashed twice with 1N HCl, then with H₂O, sat. NaHCO₃, and sat. NaCl.Drying over MgSO₄ and removal of the solvent under reduced pressuregives the crude product. Chromatography on silica gel, eluting withhexane/EtOAc (95:5) gives 2.73 g (45.7% yield) of the product as an oil.The structure is confirmed by NMR and mass spectroscopy. MS: m/z 339[M+H]⁺.

[0862] 6. Ethyl 3-[3-methoxy-2-(2-phenylpropyl)phenyl]propanoate

[0863] A solution of 2.67 g (7.9 mmol) of the unsaturated ester of step5 in 50 mL EtOH is treated with 0.5 g of 10% Pd/C and reduced withhydrogen at 25° C. and 50 psi. The mixture is filtered and the solventremoved under reduced pressure giving 2.63 g (96% yield) of the productas a clear oil. The structure is confirmed by NMR and mass spectroscopy.

[0864] 7. 3-[3-Methoxy-2-(2-phenylpropyl)phenyl]propanoic Acid

[0865] A solution of 2.63 g (7.7 mmol) of the ester of step 6 in 30 mLMeOH is treated with a solution of 1.0 g (23.2 mmol) of NaOH in 10 mLH₂O and the reaction mixture is heated at reflux for 1 hour. The solventis removed under reduced pressure and the residue taken up in H₂O, andacidified to the Congo red end point with dil. HCl. The mixture isextracted with EtOAc and the EtOAc washed with sat. NaCl. Drying overMgSO₄ and removal of the solvent under reduced pressure gives 2.41 g(100% yield) of the product as an oil. The structure is confirmed by NMRand mass spectroscopy.

[0866] 8. 6-Methoxy-5-(2-phenylpropyl)-2,3,4-trihydronaphthalen-1-one

[0867] A solution of 2.41 g (7.9 mmol) of the acid of step 7 in 30 mLCH₂Cl₂ is cooled in an ice bath and treated dropwise with 7.0 mL oftrifluoracetic anhydride. The solution is kept at 0° C. for 1 hour, thenat room temperature for 1 hour. The solution is diluted with Et₂O and 5%NaOH is added cautiously until the mixture is basic. The layers areseparated and the organic phase washed with 5% NaOH, then sat. NaCl.Drying over MgSO₄ and removal of the solvent under reduced pressureleaves 2.75 g of the crude product. This is taken up in 20 mL MeOH and10 mL dioxane and treated with 6 mL of 2N_NaOH. After stirring for 1hour at room temperature, the mixture is diluted with Et₂O and thelayers separated. The Et₂O is washed with sat. NaCl, dried over MgSO₄,and the solvent removed under reduced pressure leaving 2.27 g (100%yield) of the product as an oil which crystallizes on standing. Thestructure is confirmed by NMR and mass spectroscopy.

[0868] 9. 6-Hydroxy-5-(2-phenylpropyl)-2,3,4-trihydronaphthalen-1-one

[0869] Under nitrogen, a solution of 2.27 g (7.7 mmol) of the methoxycompound of step 8 in 18 mL DMSO is treated with 1.9 g (38.6 mmol) ofcrushed NaCN and the solution is heated at 180° C. overnight. Themixture is poured into H₂O and acidified to the Congo red end point withdil. HCl. The brown solid that forms is collected and washed with H₂O.This is taken up in Et₂O with a small quantity of acetone and extractedwith 5% NaOH. The NaOH solution is washed with Et₂O and the NaOHsolution acidified with dil. HCl. The mixture is extracted with EtOAcand the EtOAc washed with sat. NaCl. Drying over MgSO₄ and removal ofthe solvent under reduced pressure left 1.7 g (78.7% yield) of theproduct as a brown oil. The structure is confirmed by NMR and massspectrometry.

[0870] 10.6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-phenylpropyl)-2,3,4-trihydronaphthalen-1-one

[0871] Under nitrogen, a solution of 1.7 g (6.1 mmol) of the phenol, 1.3g (6.7 mmol) of ®-1-phenyl-2-(1-imidazoyl)ethanol, and 1.91 g (7.3 mmol)of triphenylphosphine in 30 mL THF is treated dropwise over 15 minuteswith a solution of 1.2 mL (7.3 mmol) of diethyl azodicarboxylate in 10mL THF. After stirring at room temperature for 3 days, the mixture isdiluted with CH₂Cl₂ and washed with H₂O, then sat. NaCl. Drying overMgSO₄ and removal of the solvent under reduced pressure leaves 3.51 g ofthe crude product. Two chromatographies on silica gel, eluting withCH₂Cl₂/acetone (80:20) gives 0.75 g (27.5% yield) of final product(Compound 44) as a white foam.

[0872] Calcd for C₃₀H₃₀N₂O-0.2 acetone (MW 462.17): Theory: C, 79.52 H,6.80 N, 6.06. Found: C, 79.17 H, 6.70 N, 6.36.

EXAMPLE 44a

[0873]

[0874] Synthesis of6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(2-thiophen-3-yl-ethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 44a)

[0875] 1-3. [3-Methoxy-2-(2-thiophen-3-yl-ethyl)-phenyl]-methanol

[0876] Using the method of example 44, steps 1-3, with2-(2,3-dimethoxyphenyl)-4,4-dimethyl-2-oxazoline (J. Org. Chem. 43, 1372(1978) and the Grignard reagent prepared from1-bromo-2-(3-thiophenyl)ethane and magnesium the title compound wasprepared and the structure confirmed by NMR spectroscopy.

[0877] 4. 3-[2-(2-Bromomethyl-6-methoxy-phenyl)-ethyl]-thiophene

[0878] A solution of 20.8 g (83.8 mmol) of[3-methoxy-2-(2-thiophen-3-yl-ethyl)phenyl]-methanol in 200 mL THF wastreated with 16.6 g (83.8 mmol) of BaCO₃ and cooled in ice. This wasthen treated dropwise rapidly with 6.0 mL (62.8 mmol) of PBr₃. Afterstirring at 0° for 15 min., the mixture was stirred at room temperatureovernight. The mixture was diluted with EtOAc, separated and the aqueuoslayer washed with EtOAc. The combined organic layers were washed withwater, sat. NaHCO₃, and then with sat. NaCl. Drying over MgSO₄ andremoval of the solvent under reduced pressure left 27.2 g (99% yield) ofthe product as an oil. The structure was confirmed by NMR and massspectroscopy.

[0879] 5. 2-[3-Methoxy-2-(2-thiophen-3-yl-ethyl)-phenyl]-malonic AcidDimethyl Ester

[0880] To a solution of 75 mL MeOH was added 2.0 g (83.6 mmol) of sodiumpellets, when all the sodium was consumed, 9.6 mL (83.6 mmol) ofdimethyl malonate was added. After stirring at room temperature for 0.5h, a solution of 26.0 g (83.6 mmol) of3-[2-(2-Bromomethyl-6-methoxy-phenyl)-ethyl]-thiophene in 100 mL MeOHwas added dropwise. After stirring for 15 min. at room temperature themixture was refluxed overnight. The mixture diluted with EtOAc andwashed with 1N HCl, H₂O, sat. NaHCO₃, and sat. NaCl. Drying over MgSO₄and removal of the solvent under reduced pressure left 27.9 g (92%yield) of a golden oil. The structure was confirmed by NMR and massspectroscopy.

[0881] 6. [3-Methoxy-2-(2-thiophen-3-yl-ethyl)-phenyl-acetic Acid

[0882] A solution of 27.9 g (7.7 mmol) of2-[3-Methoxy-2-(2-thiophen-3-yl-ethyl)phenyl]-malonic acid dimethylester in 150 mL MeOH and 150 mL dioxane was treated with a solution of15 g (0.385 mol) of NaOH in 200 mL H₂O and heated at reflux overnight.The solvent was reduced to half volume, diluted with H₂O and extractedtwice with Et₂O. The aqueous layer acidified to the Congo red point withdil. HCl. The mixture was extracted with EtOAc and the EtOAc washed withsat. NaCl. Drying over MgSO₄ and removal of the solvent under reducedpressure gave 25.95 g of a yellow oil. The oil was taken up in 200 mLdioxane and heated at reflux overnight. Removal of solvent then affordeda 21.4 g (96% yield) of a brown oil. The structure was confirmed by NMRand mass spectroscopy.

[0883] 7. 2-[3-Methoxy-2-(2-thiophen-3-yl-ethyl)-phenyl]-ethanol

[0884] Lithium aluminum hydride (5.5 g, 0.147 mol) was suspended in 80mL of THF. To the suspension was added dropwise a solution of[3-Methoxy-2-(2-thiophen-3-yl-ethyl)-phenyl]-acetic acid (21.4 g, 0.074mol) in THF. The mixture was stirred at room temperature for 15 min.then refluxed for 5 h. The mixture was then adjusted to pH 8 by theaddition of 1N sulfuric acid and diluted with EtOAc. The organic phasewas washed with 1NH₂SO₄, H₂O, saturated sodium bicarbonate, brine anddried over anhydrous magnesium sulfate. The solution was concentrated toyield a golden oil (18.18 g, 89% yield) which crystallized on standing.The structure was confirmed with MS and NMR spectroscopy.

[0885] 8. 3-{2-[2-(2-Bromo-ethyl)-6-methoxy-phenyl]-ethyl}-thiophene

[0886] A solution of 18.18 g (0.0658 mol) of2-[3-Methoxy-2-(2-thiophen-3-yl-ethyl)-phenyl]-ethanol in 300 mL CH₂Cl₂was treated with 17.43 g (0.0658 mol) of triphenylphosphine followed by11.95 g (0.0658 mol) of recrystallized N-bromosuccinimide which wasadded in portions. After stirring at room temperature overnight, thesolution was filtered through a plug of flash silica gel. The filtratewas concentrated to a golden oil and taken up in Et₂O/hexane. The solidtriphenylphosphine oxide was filtered and the solution concentrated andEt₂O/hexanne treatment repeated to afford a golden oil (20.58 g, 92%yield). The structure was confirmed by NMR and mass spectroscopy.

[0887] 9. 3-[3-Methoxy-2-(2-thiophen-3-yl-ethyl)-phenyl]-propionitrile

[0888] A solution of 20.58 g (0.0607 mol) of3-{2-[2-(2-Bromo-ethyl)-6-methoxyphenyl]-ethyl}-thiophene in 100 mLacetone and 100 mL EtOH was treated with a solution of 4.7 g (0.0728mol) of KCN in 50 mL H₂O and heated at reflux overnight. The mixture wasconcentrated and diluted with EtOAc; washed 2 times with H₂O, then sat.NaCl. Drying over MgSO₄ and removal of the solvent under reducedpressure left 18.2 g (100% yield) of the product as a golden oil. Thestructure was confirmed by NMR and mass spectroscopy.

[0889] 10. 3-[3-Methoxy-2-(2-thiophen-3-yl-ethyl)-phenyl]-propionic Acid

[0890] A solution of 17.3 g (0.0606 mol) of3-[3-Methoxy-2-(2-thiophen-3-yl-ethyl)-phenyl]-propionitrile in 200 mLEtOH was treated with a solution of 13.0 g (0.324 mol) of NaOH in 70 mLH₂O and heated at reflux overnight. The solvent was removed underreduced pressure and the residue taken up in H₂O and washed with CH₂Cl₂then Et₂O. The mixture was acidified with dil. HCl to congo red pointand extracted 2 times with CH₂Cl₂. The organic layer was washed withsat. NaCl. Drying over MgSO₄ and removal of the solvent under reducedpressure left 14.34 g (78% yield) of the product as a golden oil. Thestructure was confirmed by NMR and mass spectroscopy.

[0891] 11-13.(S)-6-(2-Imidazol-1-yl-1S-phenyl-ethoxy)-5-[2-(3-thiophenyl)-ethyl]-3,4-dihydro-2H-naphthalen-1-one

[0892] Using the procedures of example 44 steps 8-10 the title compoundwas prepared from3-[3-Methoxy-2-(2-thiophen-3-yl-ethyl)-phenyl]-propionic acid. Theproduct was isolated as a white fluffy powder 1.21 g (20% yield 3steps).

[0893] Calcd for C₂₇H₂₆N₂O₂S.HCl.0.6H₂O (MW 489.77) C, 66.21H, 5.80 N,5.72

[0894] Found C, 66.16H, 5.73 N, 5.41

EXAMPLE 44b

[0895]

[0896] Synthesis of6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(3-phenyl-propyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 44b)

[0897] The title compound was prepared according to the procedure forexample 44a steps 1-13, with2-(2,3-dimethoxyphenyl)-4,4-dimethyl-2-oxazoline (J. Org. Chem. 43, 1372(1978) and the Grignard reagent prepared from 1-bromo-3-phenyl-propaneand magnesium. The title compound was obtained as a tan foam and thestructure confirmed by NMR spectroscopy. Calcd for C₃₀H₃₀N₂O₂.0.1CH₂Cl₂(MW 459.05) C, 78.75; H, 6.63 N, 6.10

[0898] Found C, 78.72; H, 6.65 N, 5.95

EXAMPLE 45

[0899] Synthesis of6-((1S)-2-imidazolyl-1-phenylethoxy)-5-benzyl-2,3,4-trihydro-naphthalen-one(Compound 45)

[0900] 1. N-(2-Hydroxy-1,1-dimethylethyl)-3-methoxybenzamide

[0901] 2-Amino-2-methyl-1-propanol (80.23 g, 0.9 mol) is dissolved indichloromethane (180 mL) and cooled to 5° C., followed by the additionof 3-methoxybenzyl chloride (76.8 g, 0.45 mol) in dichloromethane (150mL) over 1 hour at 5° C. The mixture is warmed to 25° C. over 3 hours,filtered, and the filtrate is evaporated to an oil. The oil is taken upinto ethyl ether, washed with 1N citric acid and then brine, and driedover anhydrous magnesium sulfate. The suspension is filtered andevaporated to an oil which solidifies (93.0 g, 93% yield). NMR spectrumis consistent with structure.

[0902] MS: APCI: M+1, 224.1 (M: 223.3).

[0903] 2. 2-(3-Methoxyphenyl)-4,4-dimethyloxazolidine

[0904] To N-(2-Hydroxy-1,1-dimethylethyl)-3-methoxybenzamide (93 g, 0.42mol) is added thionyl chloride (98 g, 1.25 mol) in portions over 1 hour.After stirring for 30 minutes, the excess thionyl chloride is evaporatedin vacuo giving a solid. With cooling, the solid is dissolved in amixture of ethyl ether (1 L) and 20% NaOH solution. The mixture isagitated and the phases separated. The aqueous phase is extracted withethyl ether, which is combined with the preceding ether phase. This iswashed with brine, dried over anhydrous magnesium sulfate, filtered andevaporated to an oil (82 g, 96% yield). NMR spectrum is consistent withstructure.

[0905] 3. 6-(4,4-Dimethyl(1,3-oxazolin-2-yl))-2-methoxyphenyl PhenylKetone

[0906] 2-(3-Methoxyphenyl)-4,4-dimethyloxazolidine (30.79 g, 0.15 mol)is dissolved in dry tetrahydrofuran (600 mL) followed by cooling to −60°C. To the mixture is added n-butyllithium, (1.6 M in hexane, 100 mL)over 10 minutes. The mixture is stirred at −50° C. for 2 hours, followedby cooling to −60° C. and the addition of a solution of benzoyl chloride(22 g, 0.15 mol) in tetrahydrofuran (100 mL) over 10 minutes. Afterstirring for 3 hours at −50° C., the mixture is evaporated to a solidand dissolved in a mixture of ethyl acetate and water. The phases areseparated, and the organic phase is washed with brine, dried overanhydrous magnesium sulfate, filtered and the filtrate reduced in volumein vacuo. Addition of ethyl ether gives a crystalline precipitate thatis filtered and dried to a white solid (34 g, 73% yield).

[0907] NMR spectrum is consistent with structure.

[0908] MS: APCI: M+1, 310.3 (M: 309.4).

[0909] 4. 2-Benzoyl-3-methoxybenzoic Acid

[0910] 6-(4,4-Dimethyl(1,3-oxazolin-2-yl))-2-methoxyphenyl phenyl ketone(34 g, 0.11 mol) is dissolved in 18% HCl (700 mL) and heated to 110° C.for 18 hours. A suspended solid is filtered off. The filtrate isextracted with ethyl acetate, and the previously filtered solid isdissolved in the ethyl acetate extract. The organic phase is washed with1N citric acid and then brine, and dried over anhydrous magnesiumsulfate. The suspension is filtered and evaporated to a solid (22.1 g,78% yield). NMR spectrum is consistent with structure. MS: APCI: M+1,257.1 (M: 256.3).

[0911] 5. 2-Benzyl-3-methoxy-benzoic Acid

[0912] To methanol (500 mL) is added 2-benzoyl-3-methoxybenzoic acid(21.9 g, 0.085 mol) and 20% palladium on carbon catalyst (2.0 g),followed by pressurization of the mixture to 47 psi with hydrogen gas.After 23 hours, the mixture is filtered and the filtrate is evaporatedto 100 mL in volume in vacuo. Addition of ethyl ether gives acrystalline solid which is filtered and dried (13 and 14 g, 63% yield).NMR spectrum is consistent with structure. MS: APCI: M-1, 241.0 (M:242.3).

[0913] 6. (2-Benzyl-3-methoxyphenyl)methanol

[0914] A solution of6-((S)-2-imidazol-1-yl-1-phenylethoxy)-5-phenethyl-2,3,4-trihydronaphthalen-1-one(13.5 g, 0.056 mol) in tetrahydrofuran (100 mL) is added to a solutionof lithium aluminum hydride (4.27 g, 0.112 mol) in tetrahydrofuran (250mL) over 30 minutes. The mixture is stirred for 2 hours followed byheating to 70° C. for 3 hours and stirring at 25° C. for 18 hours. Themixture is then cooled to −40° C., and the pH is adjusted to 8 by theaddition of 6N sulfuric acid. The resulting solid is filtered, washedwith ethyl acetate and the filtrates combined. The organic phase isevaporated to an oil, dissolved in ethyl ether, washed with saturatedsodium bicarbonate and then brine, and dried over anhydrous magnesiumsulfate. The suspension is filtered and evaporated to a solid (12.5 g,98% yield). NMR spectrum is consistent with structure. MS: APCI: M+1,516.1 (dimer) (M: 228.3).

[0915] 7. 3-(Chloromethyl)-1-methoxy-2-benzylbenzene

[0916] (2-Benzyl-3-methoxyphenyl)methanol (12.5 g, 0.055 mol) and bariumcarbonate (14.5 g, 0.073 g) are suspended in dichloromethane (120 mL)followed by cooling to 2° C. A solution of thionyl chloride (5.4 mL,0.073 mol) in dichloromethane (100 mL) is added. The mixture is stirredat 25° C. overnight, filtered, and evaporated to an oil. Addition ofethyl ether and hexane gives a solid (11.74 g, 86.5% yield). NMRspectrum is consistent with structure. MS: APCI: M+1, 246.1 (M: 246.7).

[0917] 8. Ethyl (2E)-4-[3-methoxy-2-benzylphenyl]but-2-enoate

[0918] 1-(Chloromethyl)-3-methoxy-2-(phenylmethyl) benzene (13.5 g,0.055 mol), tri-n-butylamine (36 mL), ethyl acrylate (18 mL) andpalladium acetate (0.247 g, 1.23 mmol) are mixed and sparged withnitrogen gas, followed by heating to 100° C. for 18 hours. To themixture is then added palladium acetate (0.5 g, 2.5 mmol) and ethylacrylate (9 mL) followed by additional heating at 100° C. for 18 hours.The mixture is then filtered at 45μ to remove catalyst and the filtrateis taken up into ethyl ether. The solution is washed with 1N HCl andthen brine before being dried over anhydrous magnesium sulfate. Thefiltrate is evaporated to an oil that is purified by silica gelchromatography, eluted with a mixture of ethyl acetate/hexane (15:85).The product is recovered as a syrup (6.8 g, 40% yield). NMR spectrum isconsistent with structure. MS: APCI: M+1, 311.1 (M: 310.4).

[0919] 9. Ethyl 4-(2-benzyl-3-methoxyphenyl)butanoate

[0920] Ethyl (2E)-4-[3-methoxy-2-benzylphenyl]but-2-enoate (6.8 g, 0.022mol), and 10% palladium on carbon catalyst (1.0 g) are added to absoluteethanol (100 mL) and pressurized to 51 psi with hydrogen gas for 22hours. The mixture is filtered and evaporated to a crude oil (6.8 g)which is used in the following synthesis without further purification.

[0921] 10. 4-(2-Benzyl-3-methoxyphenyl)butanoic Acid

[0922] Ethyl 4-(2-benzyl-3-methoxyphenyl)butanoate (6.58 g, 0.021 mol)and sodium hydroxide (4.9 g, 0.122 mol) are added to a mixture of water(20 mL) and dioxane (30 mL) followed by heating at 80° C. for 1 hour.The mixture is evaporated to a solid, upon which water is added,followed by evaporation in vacuo to a suspension. The solid is filtered,and the filtrate is washed with ethyl ether. The aqueous phase isacidified to pH 1 with conc. HCl and extracted with ethyl ether. Theether is washed with brine, dried over anhydrous magnesium sulfate, andfiltered.

[0923] The filtrate is evaporated to a crystalline solid (4.83 g, 81%yield). NMR spectrum is consistent with structure. MS: APCI: M-1, 281.3(M: 284.4).

[0924] 11. 5-Benzyl-6-methoxy-2,3,4-trihydronaphthalen-1-one

[0925] 4-(2-Benzyl-3-methoxyphenyl)butanoic acid (4.39 g, 0.015 mol) isdissolved in ethanol-free chloroform (30 mL) and polyphosphate ester(prepared as described in J. Organic Chemistry, 1969;34(9):2666) (8 g)is added. The flask is sealed and kept in the dark for 18 hours at 25°C. The mixture is extracted with water, and the chloroform phase iswashed with brine, dried over anhydrous magnesium sulfate, filtered, andevaporated to a solid. The solid is recrystallized from an ethylether/hexane mixture giving a solid (3.92 g, 95% yield). NMR spectrum isconsistent with structure. MS: APCI: M+1, 267.1 (M: 266.3).

[0926] 12. 5-Benzyl-6-hydroxy-2,3,4-trihydronaphthalen-1-one

[0927] 5-Benzyl-6-methoxy-2,3,4-trihydronaphthalen-1-one (3.86 g, 0.014mol) and sodium cyanide (3.55 g, 0.072 mol) is dissolveddimethylsulfoxide (25 mL), followed by heating at 180° C. for 5 hours.The mixture is cooled to 100° C., poured into 150 g of ice and acidifiedto pH 1 with conc. HCl. The mixture is repeatedly extracted with ethylether, washed with brine, dried over anhydrous magnesium sulfate andfiltered. The filtrate is concentrated in vacuo giving a solid uponaddition of hexane (1.85 g, 51% yield). NMR spectrum is consistent withstructure. MS: APCI: M+1, 253.1 (M: 252.3).

[0928] 13.6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-benzyl-2,3,4-trihydro-naphthalen-1-one

[0929] To tetrahydrofuran (35 mL) is added5-benzyl-6-hydroxy-2,3,4-trihydronaphthalen-1-one (1.82 g, 7.2 mmol),(R)-2-imidazol-1-yl-1-phenylethanol (1.49 g, 7.9 mmol) andtriphenylphosphine (2.55 g, 9.7 mmol). A solution ofdiethylazodicarboxylate (1.69 g, 9.7 mmol) in tetrahydrofuran (15 mL) isadded over 30 minutes. After stirring for 18 hours at 25° C., themixture is evaporated in vacuo and the residue is suspended in ethylether and 1N citric acid, washed exhaustively with ethyl ether and thepH adjusted to 5.5 with 6N NaOH. The aqueous phase is extracted withethyl ether, separated, washed with brine, dried over anhydrousmagnesium sulfate and filtered. The filtrate is evaporated to a solidwhich is purified by silica gel chromatography eluted with chloroformgiving a solid (Compound 45) (1.32 g, 43% yield). NMR spectrum isconsistent with structure.

[0930] MS: APCI: M+1, 423.1 (M: 422.5).

[0931] Calcd. For C₂₈H₂₆N₂O₂: Theory: C 76.76, H 5.98, N 6.36, Cl 3.62.Found: C 76.71, H 6.25, N 6.40, Cl 3.39.

EXAMPLE 46

[0932] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-phenoxy-2,3,4-trihydronaphthalen-1-one(Compound 46)

[0933] 1. 1-(Chloromethyl)-2,3-dimethoxybenzene

[0934] 2,3-Dimethoxybenzyl alcohol (112.5 g, 0.677 mol) is dissolved inethyl ether (390 mL) and purged with anhydrous HCl gas. Upon cooling to20° C., thionyl chloride (60 mL, 0.68 mol) is added with vigorousstirring over 30 minutes. The solution is washed with cold brine,saturated sodium bicarbonate solution, and brine. The organic phase isdried over anhydrous magnesium sulfate, filtered, and concentrated invacuo to an oil (125 g). The oil is distilled at 3 mm Hg, Bp. 105-112°C. (99 g, 79% yield). NMR spectrum is consistent with structure.

[0935] 2. Ethyl (2E)-4-(2,3-dimethoxyphenyl)but-2-enoate

[0936] 1-(Chloromethyl)-2,3-dimethoxybenzene (87.3 g, 0.47 mol), ethylacrylate (77 mL, 0.709 mol), and palladium acetate (2.27 g, 9.4 mmol)are added to tri-n-butylamine (175 g, 0.946 mol) and heated to 100° C.for 18 hours. The mixture is filtered through celite, and the filtrateis partitioned between ethyl ether and 1N citric acid. The ether phaseis separated and washed with 1N citric acid to remove the amine, washedwith brine, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate is evaporated to an oil (109.2 g, 92% yield). NMR spectrum isconsistent with structure.

[0937] 3. Ethyl 4-(2,3-dimethoxyphenyl)butenoate

[0938] Ethyl (2E)-4-(2,3-dimethoxyphenyl)but-2-enoate (109.2 g, 0.436mol) and 10% palladium on carbon catalyst (10 g) are added to absoluteethanol (1 L) and pressurized to 47 psi for 18 hours. The mixture isfiltered, and the filtrate is evaporated to an oil (106.4 g, 96% yield).NMR spectrum is consistent with structure. MS: APCI: M+1, 253.2 (M:252.3).

[0939] 4. 4-(2,3-Dimethoxyphenyl)butanoic Acid

[0940] Ethyl 4-(2,3-dimethoxyphenyl)butenoate (106.4 g, 0.42 mol) and 1Nsodium hydroxide (800 mL) are added to methanol (400 mL) followed byheating at reflux for 2 hours. The mixture is evaporated to an oil,which is washed with ethyl ether and acidified to pH 1 with conc. HCl.The mixture is then extracted with ethyl ether, washed with brine, driedover anhydrous magnesium sulfate, and filtered. The filtrate isevaporated to a crystalline solid (90.36 g, 96% yield). NMR spectrum isconsistent with structure. MS: APCI: M+1, 225.2 (M: 224.3).

[0941] 5. 5,6-Dimethoxy-3,4-dihydro-2H-naphthalen-1-one

[0942] 4-(2,3-Dimethoxyphenyl)butanoic acid (90.1 g, 0.40 mol) isdissolved in ethanol-free chloroform (400 mL) and polyphosphate ester(J. Organic Chemistry, 1969;34(9):2666) (225 g) is added. The flask issealed and kept in the dark for 42 hours at 25° C. The mixture isextracted with water, and the chloroform phase is washed with brine,dried over anhydrous magnesium sulfate, filtered, and evaporated to asolid (70.5 g, 85% yield). NMR spectrum is consistent with structure.MS: APCI: M+1, 207 (M: 206.2).

[0943] 6. 5-Hydroxy-6-methoxy-2,3,4-trihydronaphthalen-1-one

[0944] 5,6-Dimethoxy-2,3,4-trihydronaphthalen-1-one (73.3 g, 0.36 mol)and methionine (116.6 g, 0.8 mol) are added to 98% methanesulfonic acid(920 mL) followed by stirring at 25° C. for 66 hours. The mixture ispoured into ice water (4 L) with rapid stirring, giving a solid that isfiltered, washed with water, and allowed to air dry. The solid isdissolved in warm ethyl acetate, washed with brine, dried over anhydrousmagnesium sulfate, and filtered. The filtrate is evaporated to give asolid upon addition of ethyl ether (45.23 g, 66% yield). NMR spectrum isconsistent with structure. MS: APCI: M+1, 193.1 (M: 192.2).

[0945] 7. 5-Phenoxy-6-methoxy-2,3,4-trihydronaphthalen-1-one

[0946] 5-Hydroxy-6-methoxy-2,3,4-trihydronaphthalen-1-one (6.96 g, 0.038mol), copper acetate (10.54 g, 0.058 mol), triphenylbismuth (18.3 g,0.042 mol), and triethylamine (5.78 mL, 0.042 mol) are added totetrahydrofuran (75 mL) followed by heating to 50° C. for 10 hours andstirring at 25° C. for 48 hours. The mixture is filtered, and thefiltrate is evaporated to an oil which is taken up into a mixture ofethyl ether and water. The organic phase is washed with 1N sodiumhydroxide, brine, 1N HCl, and brine again. The organic phase is driedover anhydrous magnesium sulfate, filtered, and evaporated to an oilwhich is crystallized from a mixture of ethyl acetate and ethyl ether(6.0 g, 59% yield). NMR spectrum is consistent with structure. MS: APCI:M+1,269.1 (M: 268.3).

[0947] 8. 5-Phenoxy-6-hydroxy-2,3,4-trihydronaphthalen-1-one

[0948] 5-Phenoxy-6-methoxy-2,3,4-trihydronaphthalen-1-one (6.0 g, 0.022mol) and sodium cyanide (5.48 g, 0.11 mol) is dissolved indimethylsulfoxide (25 mL), followed by heating at 180° C. for 4 hours.The mixture is poured into ice and acidified to pH 1 with conc. HCl. Themixture is repeatedly extracted with ethyl ether, which is washed withbrine, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate is concentrated in vacuo giving a solid (3.53 g, 62% yield).NMR spectrum is consistent with structure. MS: APCI: M+1, 255.1 (M:254.3).

[0949] 9.(S)-6-(2-Imidazol-1-yl-1-phenyl-ethoxy)-5-phenoxy-3,4-dihydro-2H-naphthalen-1-one

[0950] To tetrahydrofuran (35 mL) is added5-phenoxy-6-hydroxy-2,3,4-trihydronaphthalen-1-one (1.8 g, 7.1 mmol),(R)-2-imidazol-1-yl]-phenylethanol (1.48 g, 7.9 mmol) andtriphenylphosphine (2.59 g, 10 mmol). A solution ofdiethylazodicarboxylate (1.66 g, 9.6 mmol) in tetrahydrofuran (15 mL) isadded over 30 minutes. After stirring for 3 hours at 25° C., the mixtureis evaporated in vacuo, and the residue is suspended in ethyl ether and1N citric acid, washed exhaustively with ethyl ether, and the pHadjusted to 6 with 4N NaOH. The aqueous phase is extracted with ethylacetate, which is separated, washed with brine, dried over anhydrousmagnesium sulfate, and filtered. The filtrate is evaporated to a solidwhich is purified by silica gel chromatography eluted with chloroformgiving a solid (Compound 46) (1.38 g, 46% yield). NMR spectrum isconsistent with structure. MS: APCI: M+1, 425.1 (M: 424.5).

[0951] Calcd. for C₂₇H₂₄N₂O₃: Theory: C 73.71, H 5.50, N 6.33, Cl 3.60.Found: C 76.57, H 5.85, N 6.65, Cl 2.37.

EXAMPLE 47

[0952] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-4-(3-chlorophenyl)-2,3,4-trihydronaphthalen-1-one(Compound 47)

[0953] 1. 1-(3-Chlorophenyl)-7-methoxy-1,2,3,4-tetrahydronaphthol

[0954] Milligram shavings (1.65 g, 0.68 mol) are suspended in diethylether (60 mL). A small quantity of 12 crystals and 3-bromochlorobenzeneare added. The reaction mixture is refluxed for 2 hours before theaddition of 7-methoxy-1-tetralone (10 g, 0.057 mol). The reaction isrefluxed for an additional 2 hours. 1N HCl is poured into the flask andthe layers two resulting layers are separated. The organic layer iswashed with 1N HCl and then brine, dried over MgSO₄, and the solventremoved in vacuo. Chromatography using 20% hexane/DCM to 10% hexane/DCMaffords a clear colorless oil (8.5 g, 52% yield). NMR (CDCl₃); MS: APCI271 [M-17].

[0955] 2. 4-(3-Chlorophenyl)-6-methoxy-1,2-dihydronaphthalene

[0956] 1-(3-Chlorophenyl)-7-methoxy-1,2,3,4-tetrahydronaphthol (8.5 g,0.03 mol) is dissolved in benzene. p-Toluenesulfonic acid (0.04 g, 0.2mmol) is added before a Dean-Stark trap is attached, and the reaction isrefluxed 2 hours. The reaction mixture is washed with sat. NaHCO₃solution and then brine, dried over MgSO₄, and the solvent removed invacuo (7.37 g, 91% yield). NMR (CDCl₃); MS: APCI 271 [M+1].

[0957] 3. 1-(3-Chlorophenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene

[0958] 4-(3-Chlorophenyl)-6-methoxy-1,2-dihydronaphthalene (7.3 g, 0.027mol) is dissolved in ethanol (100 mL) and placed in a Parr shaker. 10%Pd/C (0.5 g) and 5 drops concentrated HCl are added. The reaction isplaced under a hydrogen atmosphere with ΔP_(calc.)=24.8#, andΔP_(obs.)=24.3#. Solvent is removed in vacuo to afford a yellow oil(7.34 g, 100% yield). NMR (CDCl₃); MS: APCI 273 [M+1].

[0959] 4. 4-(3-Chlorophenyl)-6-methoxy-1-tetralone

[0960] 1-(3-Chlorophenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene (1.2g, 4.4 mmol) is dissolved in glacial acetic acid (20 mL) and heated to80° C. Chromium trioxide (0.57 g, 5.7 mmol) in acetic acid (2.5mL)/water (1 mL) is added to the hot mixture. The reaction mixture isheated for 2 hours at 80° C. Solvent is removed in vacuo. The residue ispartitioned between EtOAc and water. Organic layer is washed withsaturated NaHCO₃ solution, brine, dried over MgSO₄ and solvent removedin vacuo. Chromatographed the oil using EtOAc 30%/Hexane giving an amberoil (0.85 g, 70%). NMR (CDCl₃); MS: APCI 287.1 [M+1].

[0961] 5. 4-(3-Chlorophenyl)-6-hydroxy-1-tetralone

[0962] 4-(3-Chlorophenyl)-6-methoxy-1-tetralone (0.85 g, 3 mmol) isdissolved in DMSO (10 mL). Crushed NaCN (0.73 g, 15 mmol) is added, andthe reaction is heated at 180° C. overnight. The reaction is then pouredinto water (70 mL) and acidified to pH 2 using concentrated HCl. Theresulting brown solid (0.8 g, 100% yield) is filtered and dried in avacuum oven at 50° C. for 2 hours. NMR (CDCl₃); MS: APCI 273.1 [M+1].

[0963] 6.6-((1S)-2-Imidazolyl-1-phenylethoxy)-4-(3-chlorophenyl)-2,3,4-trihydronaphthalen-1-one

[0964] 4-(3-Chlorophenyl)-6-hydroxy-1-tetralone (0.8 g, 3.0 mmol),[1-R-phenyl-2-(1-imidazole)ethanol] (0.62 g, 3.5 mmol), andtriphenylphosphine (1.16 g, 4.4 mmol) are dissolved in dry THF (20 mL).DEAD reagent (0.68 mL, 4.4 mmol) is added, and the reaction is stirredovernight. Solvent is removed in vacuo. 1N HCl is added, and thereaction mixture is washed several times with diethylether. The aqueouslayer is neutralized by adding 1N NaOH and extracting with EtOAc. Theorganic layer is washed with sat. NaHCO₃ solution and then brine, driedover MgSO₄, and the solvent removed in vacuo. Chromatography using DCMto DCM/MeOH 2% yields a yellow/orange foam (Compound 47) (0.62 g, 50%yield). NMR (CDCl₃); MS: APCI 443.1 [M+1].

[0965] Anal. Calcd. C₂₇H₂₃N₂Cl₁O₂.0.13 mol DCM, MWC=453.99:

[0966] Theory: C, 71.78; H, 5.16; N, 6.17.

[0967] Found: C, 71.75; H, 5.11; N, 6.92.

EXAMPLE 48

[0968] Synthesis of(±)-6-(2-imidazolyl-O-phenylethoxy)-4-phenyl-2,3,4-trihydronaphthalen-1-one(Compound 48)

[0969] 1. Methyl 3-(3-methoxyphenyl)-3-phenylprop-2-enoate

[0970] To a solution of 21.73 g (0.1024 mol) of 3-methoxybenzophenoneand 10.7 mL (0.1126 mol) of methyl bromoacetate in 200 mL benzene isadded 8.4 g (0.128 g—atom of acid washed granular Zn. A crystal of I₂ isadded and the mixture heated. The mixture is heated at reflux for anadditional hour, then decomposed with 12% HCl. The layers are separatedand the benzene layer washed 4 times with H₂O, then sat. NaHCO₃, andfinally sat NaCl. Drying over MgSO₄ and removal of the solvent underreduced pressure leaves 30.12 g of a yellow oil.

[0971] This yellow oil is taken up in 100 mL Ac₂O and heated at refluxfor 1 hour. The Ac₂O is removed under reduced pressure and the residuetaken up in Et₂O and washed 3 times with sat. NaHCO₃ and then sat. NaCl.Drying over MgSO₄ and removal of the solvent under reduced pressureaffords 28.1 g of a brown oil. Distillation under reduced pressure gives25.06 g (91.2% yield) of the product or a 1:1 mixture of double boundisomers. The structure is confirmed by NMR and mass spectroscopy.

[0972] 2. Methyl 3-(3-methoxyphenyl)-3-phenylpropanoate

[0973] A solution of 25.0 g (0.0932 mol) of the unsaturated ester ofstep 1 in 600 mL MeOH is treated with 2 g of 20% Pd/C and reduced at 27°C./50 psi of H₂. Removal of the solvent under reduced pressure leaves24.1 g (95.8% yield) of the product as a golden oil. The structure isconfirmed by NMR spectroscopy.

[0974] 3. 3-(3-Methoxyphenyl)-3-phenylpropan-1-ol

[0975] To a suspension of 5.1 g (0.134 mol) of LAH in 100 mL THF isadded dropwise a solution of 24.12 g (0.0892 mol) of the ester from step2 in 200 mL THF. The mixture is stirred at room temperature for 0.5hour, then heated at reflux for 2 hours. The mixture is decomposed with1N H₂SO₄, diluted with EtOAc, and the layers separated. The organicphase is washed with 1N H₂SO₄, H₂O, sat. NaHCO₃, and sat. NaCl. Dryingover MgSO₄ and removal of the solvent under reduced pressure leaves21.46 g (99.4% yield) of the product as a pale yellow oil. The structureis confirmed by NMR and mass spectroscopy.

[0976] 4. 3-(3-Bromo-1-phenylpropyl)-1-methoxybenzene

[0977] A solution of 21.46 g (0.0886 mol) of the alcohol from step 3 in350 mL CH₂Cl₂ is treated with 23.23 g (0.0886 mol) of triphenylphosphinefollowed by 15.77 g (0.0886 mol) of recrystallized N-bromosuccinimidewhich is added in portions. After stirring at room temperature for 2hours, the solution is filtered through a plug of flash silica gel. Thefiltrate is passed through silica gel again and the solvent then removedunder reduced pressure leaving 27.0 g (100% yield) of the product as apale yellow oil. The structure is confirmed by NMR spectroscopy.

[0978] 5. 4-(3-Methoxyphenyl)-4-phenylbutanenitrile

[0979] A solution of 27.0 g (0.0885 mol) of the bromo compound from step4 in 100 mL acetone and 100 mL EtOH is treated with a solution of 6.9 g(0.106 mol) of KCN in 100 mL H₂O, and the reaction is heated at refluxovernight. The solvent is removed under reduced pressure and the residuetaken up in EtOH and washed 3 times with H₂O and then sat. NaCl. Dryingover MgSO₄ and removal of the solvent under reduced pressure leaves22.23 g (100% yield) of the product as a yellow oil. The structure isconfirmed by NMR and mass spectroscopy.

[0980] 6. 4-(3-Methoxyphenyl)-4-phenylbutanoic acid

[0981] A solution of 22.23 g (0.0885 mol) of the nitrile from step 5 in175 mL EtOH is treated with a solution of 17.7 g (0.442 mol) of NaOH in100 mL H₂O and heated at reflux overnight. The solvent is removed underreduced pressure and the residue taken up in H₂O and washed 2 times withEt₂O. Acidification with dil. HCl causes an oil to separate. This istaken up in EtOAc and washed with sat. NaCl. Drying over MgSO₄ andremoval of the solvent under reduced pressure leaves 21.46 g (89.8%yield) of the product as a pale yellow oil. The structure is confirmedby NMR and mass spectroscopy.

[0982] 7. (±)-6-Methoxy-4-phenyl-2,3,4-trihydronaphthalen-1-one

[0983] A solution of 10.59 g (0.0392 mol) of the acid from step 6 in 150mL CH₂Cl₂ is cooled in ice and treated dropwise with 35 mL oftrifluoroacetic anhydride. After stirring at 0° for 0.5 hour, thesolution is stirred at room temperature for 1.5 hours. The solution isdiluted with Et₂O, and H₂O is added cautiously, followed by 5% NaOH. Thelayers are separated and the organic phase washed with 5% NaOH untilbasic, then washed with sat. NaCl. Drying over MgSO₄ and removal of thesolvent under reduced pressure gives 10.4 g of a yellow oil.

[0984] The oil is taken up in 100 mL MeOH and 25 mL of 2N NaOH added andthe solution stirred at room temperature for 0.5 hour. The solution isdiluted with Et₂O and the layers separated. The Et₂O extract is washedwith sat. NaCl. Drying over MgSO₄ and removal of the solvent underreduced pressure gives 8.65 g (87.5% yield) of the product.

[0985] This is combined with material from another run andchromatographed on silica gel, eluting with CHCl₃ to afford 11.4 g ofproduct as an oil. The structure is confirmed by NMR and massspectroscopy.

[0986] 8. (±)-6-Hydroxy-4-phenyl-2,3,4-trihydronaphthalen-1-one

[0987] A solution of 11.39 g (0.0451 mol) of the methoxy tetralone fromstep 7 in 250 mL CH₂Cl₂ is cooled in ice and treated dropwise with 29 mLof BBr₃. The purple solution is kept at 0° for 0.5 hour, then at roomtemperature overnight. The solution is poured into H₂O and extractedtwice with Et₂O. The Et₂O is washed twice with 5% NaOH and the NaOH backextracted with Et₂O. The NaOH extract is acidified with dil. HCl andextracted twice with Et₂O. The Et₂O is washed with sat. NaCl, dried overMg SO₄, and the solvent removed leaving 10.82 g of a brown foam.Chromatography on silica gel, eluting with CHCl₃/MeOH (98:2) gives 2.05g (19.1% yield) of the product as a pink solid. The structure isconfirmed by NMR and mass spectroscopy.

[0988] 9.6-(2-Imidazolyl-1-phenylethoxy)-4-phenyl-2,3,4-trihydronaphthalen-1-one

[0989] Under nitrogen, a solution of 2.05 g (8.6 mmol) of the phenolfrom step 8 in 25 mL THF is treated with 1.78 g (9.5 mmol) of(R,S)-1-phenyl-2-(1-imidazoyl)ethanol and 2.26 g (8.6 mmol) oftriphenylphosphine. To this is added dropwise over 15 minutes a solutionof 1.4 mL (8.6 mmol) of diethyl azodicarboxylate in 5 mL THF. Afterstirring at room temperature overnight, the solution is diluted withEtOAc and washed 2 times with H₂O, then sat. NaHCO₃ and finally sat.NaCl. Drying over MgSO₄ and removal of the solvent under reducedpressure leaves 8.89 g of a brown oil. Two chromatographies on silicagel, eluting with CHCl₃/MeOH (98:2) gives 1.49 g (42.5% yield) of finalproduct (Compound 48) as a tan foam.

[0990] Calcd for C₂₇H₂₄N₂O₂.0.5 CHCl₃ (MW 468.17): Theory: C, 70.55 H,5.27 N, 5.98. Found: C, 70.74, H, 5.49, N, 6.55.

EXAMPLE 49

[0991] Synthesis of(±)-6-(2-imidazolyl-1-phenylethoxy)-5-prop-2-ethyl-2,3,4-trihydronaphthalen-1-one(Compound 49)

[0992] 1. 2-Imidazolyl-1-phenylethan-1-ol

[0993] Imidazole (17.6 g, 0.26 mol) is dissolved in absolute ethanol(100 mL). Pyridine (0.6 mL, 4 mmol) is added, and the mixture is heatedto reflux for 25 minutes. A solution of styrene oxide (31.1 g, 0.26 mol)in ethanol (40 mL) is added dropwise, followed by heating at reflux for18 hours. The mixture is evaporated in vacuo to a syrup and suspendedbetween ethyl ether (250 mL) and water (100 mL) giving a solidprecipitate. The suspension is filtered and then washed with water andethyl ether. The solid is dissolved in 500 mL of a mixture of hotchloroform/ethyl acetate, 70:30. The mixture is filtered, washed withbrine, dried over anhydrous magnesium sulfate, refiltered, andevaporated in vacuo to a small volume, resulting in a solid precipitate.The solid is filtered, washed with ethyl ether and dried in vacuo (17.1g, 35% yield). MS: APCI: M+1, 189.2 (M: 188.2). NMR spectrum isconsistent with structure.

[0994] 2. 6-Hydroxy-2,3,4-trihydronaphthalen-1-one

[0995] 6-Methoxytetralone (167 g, 0.95 mol, Aldrich Chem. Co.) isdissolved in 48% hydrobromic acid and heated to reflux for 5 hours.After stirring for 18 hours at 25° C., an orange solid precipitates. Thesolid is filtered, partitioned between water and ethyl ether, andfiltered off. The solid is exhaustively extracted into ethyl ether whichis evaporated to a pink solid (114 g, 74% yield). MS: APCI: M+1, 163.1(M: 162.2).

[0996] 3. 6-Prop-2-enyloxy-2,3,4-trihydronaphthalen-1-one

[0997] 6-Hydroxy-2,3,4-trihydronaphthalen-1-one, (32.44 g, 0.2 mol),anhydrous cesium carbonate (48.87 g, 0.15 mol) and allyl bromide (19 mL,0.22 mol) are added to dimethylformamide (100 mL). The mixture is heatedat 80° C. for 5 hours, followed by stirring at 25° C. for 18 hours. Thesuspension is filtered, and the filtrate is evaporated in vacuo toremove the dimethylformamide. The residue is taken up into ethyl etherand extracted with saturated sodium bicarbonate, brine, 1N citric acid,and brine, respectively. The organic phase is dried over anhydrousmagnesium sulfate, filtered through charcoal, and evaporated to an oilwhich solidifies upon standing (38 g, 95% yield). NMR spectrum isconsistent with structure. MS: APCI: M+1, 203.1 (M: 202.26).

[0998] 4. 6-Hydroxy-5-prop-2-enyl-2,3,4-trihydronaphthalen-1-one

[0999] 6-Prop-2-enyloxy-2,3,4-trihydronaphthalen-1-one (37.5 g, 0.185mol) is added to diethylaniline (100 mL) and heated to 210° C. for 18hours. The solvent is removed in vacuo giving a solid which isrecrystallized from ethyl acetate, filtered, and washed with ethergiving a solid (21.83 g, 58% yield). NMR spectrum is consistent withstructure. MS: APCI: M+1, 203.1 (M: 202.3).

[1000] 5.(±)-6-(2-Imidazolyl-1-phenylethoxy)-5-prop-2-enyl-2,3,4-trihydro-naphthalen-1-one

[1001] To tetrahydrofuran (185 mL) is added6-hydroxy-5-prop-2-enyl-2,3,4-trihydronaphthalen-1-one (1.5 g, 7.42mmol), (±)-2-imidazolyl-1-phenylethan-1-ol (1.54 g, 8.16 mmol) andtriphenylphosphine (2.14 g, 8.16 mmol). A solution ofdiethylazodicarboxylate (1.42 g, 7.4 mmol) in tetrahydrofuran (25 mL) isadded over 1 hour. After stirring for 18 hours at 25° C., the mixture isevaporated in vacuo, and the residue is suspended in ethyl ether and 1Ncitric acid, washed exhaustively with ethyl ether, and the pH adjustedto 9 with 6N NaOH. The aqueous phase is extracted with ethyl acetatewhich is separated, washed with brine, dried over anhydrous magnesiumsulfate, and filtered. The filtrate is evaporated to an oil which ispurified by chromatography on 150 g silica gel eluted with a gradient ofchloroform to 1% methanol in chloroform. The product (Compound 49) isrecovered as a foam (1.79 g, 64.6% yield). MS: APCI: M+1, 371.1 (M:372.4). NMR spectrum is consistent with structure.

[1002] Calcd. for C₂₄H₂₄N₂O₂, 1.0H₂O: Theory: C 75.92, H 6.37, N 7.38,Cl 0.00, H₂O 1.89. Found: C 75.44, H 6.65, N 7.17, Cl 0.11, H₂O 2.55.

EXAMPLE 50

[1003] Synthesis of6-(2-Imidazolyl-1-phenylethoxy)-5-propyl-2,3,4-trihydro-naphthalen-1-one(Compound 50)

[1004] 1. 6-Hydroxy-5-propyl-2,3,4-trihydronaphthalen-1-one

[1005] To tetrahydrofuran (100 mL) is added6-hydroxy-5-prop-2-enyl-2,3,4-trihydronaphthalen-1-one (Example 49, step1 2.59 g, 12.8 mol) followed by tris(triphenylphosphine)rhodium chloride(0.5 g). The mixture is pressurized to 49 psi with H₂ gas for 15 hours,with an observed uptake of H₂ gas. The mixture is filtered and thenevaporated in vacuo to a small volume after which pentane is added,resulting in a solid precipitate. The solid is filtered and dried invacuo (1.23 g, 47% yield). MS: APCI: M+1, 205.2 (M: 204.3). NMR spectrumis consistent with structure.

[1006] 2.6-(2-Imidazolyl-1-phenylethoxy)-5-propyl-2,3,4-trihydronaphthalen-1-one

[1007] To tetrahydrofuran (25 mL) is added the product from step 1 (1.1g, 5.38 mmol), (±) 2-imidazolyl-1-phenylethan-1-ol (1.11 g, 5.92 mmol),and triphenylphosphine (2.12 g, 8.08 mmol). A solution ofdiethylazodicarboxylate (1.41 g, 8.08 mmol) in tetrahydrofuran (20 mL)is added over 2 hours. After stirring for 3 hours at 25° C., the mixtureis refrigerated overnight and evaporated in vacuo to an oil. The oil issuspended in ethyl ether and 1N citric acid, washed exhaustively withethyl ether, and the pH adjusted to 13 with 6N NaOH. The aqueous phaseis extracted with ethyl ether, which is separated, washed with brine,dried over anhydrous magnesium sulfate, and filtered. The filtrate isevaporated to an oil which is purified by chromatography on 100 g silicagel eluted with a mixture of chloroform/ethyl acetate (50:50). Theproduct (Compound 50) is recovered as a gum (1.1 g, 55% yield). MS:APCI: M+1, 375.2 (M: 374.5). NMR spectrum is consistent with structure.

[1008] Calcd. for C₂₄H₂₆N₂O₂, 0.08 CHCl₃, 0.02H₂O: Theory: C 74.61, H6.89, N 7.23, Cl 2.19, H₂O 0.93. Found: C 74.77, H 6.95, N 7.37, Cl2.15, H₂O 0.78.

EXAMPLE 51

[1009] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-prop-2-enyl-2,3,4-trihydronaphthalen-1-one(Compound 51)

[1010] 1. (1R)-2-Imidazolyl-1-phenylethan-1-ol

[1011] In a manner similar to that of Example 49, step 1, imidazole(2.83 g, 41.6 mmol) is dissolved in absolute ethanol (45 mL). Pyridine(0.11 mL) is added followed by addition of (R)-(+) styrene oxide (5.0 g,41.6 mol, Aldrich Chemical Co.), followed by heating at reflux for 18hours. The mixture is evaporated in vacuo to a syrup and suspendedbetween ethyl ether (250 mL) and water (100 mL) to give a solidprecipitate. The suspension is filtered and washed with ethyl ether. Thesolid is recrystallized from hot ethyl acetate and dried in vacuo (2.52g, 32% yield). MS: APCI: M+1, 189.1 (M: 188.2). NMR spectrum isconsistent with structure.

[1012] 2.6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-prop-2-enyl-2,3,4-trihydro-naphthalen-1-one

[1013] To tetrahydrofuran (25 mL) is added the compound of Example 49,step 4 (0.79 g, 3.91 mmol), (1R)-2-imidazolyl-1-phenylethan-1-ol (0.81g, 4.3 mmol) and triphenylphosphine (1.54 g, 5.87 mmol). A solution ofdiethylazodi-carboxylate (1.02 g, 5.87 mmol) in tetrahydrofuran (20 mL)is added over 1 hour. After stirring for 2 hours at 25° C., the mixtureis evaporated in vacuo, and the residue is suspended in ethyl ether and1N citric acid, washed exhaustively with ethyl ether, and the pHadjusted to 13 with 6N NaOH. The aqueous phase is extracted with ethylether, which is separated, washed with brine, dried over anhydrousmagnesium sulfate, and filtered. The filtrate is evaporated to a solidthat is purified by chromatography on 100 g silica gel eluted with amixture of chloroform/ethyl acetate (50:50). The product (Compound 51)is recovered as a foam (0.82 g, 56% yield). MS: APCI: M+1, 373.1, (M:371.5). NMR spectrum is consistent with structure.

[1014] Calcd. for C₂₄H₂₄N₂O₂, 0.2H₂O: Theory: C 76.58, H 6.61, N 7.47,H₂O 0.98. Found: C 76.65, H 6.54, N 7.45, H₂O 0.96.

EXAMPLE 52

[1015] Synthesis of(±)-6-(2-Imidazolyl-1-phenylethoxy)-5-(2-methylprop-2-enyl)-2,3,4-trihydronaphthalen-1-one(Compound 52)

[1016] 1.6-Hydroxy-5-(2-methylprop-2-enyl)-2,3,4-trihydronaphthalen-1-one

[1017] In a manner similar to that of Example 49, step 3, the titlecompound is prepared from 6-hydroxy-2,3,4-trihydronaphthalen-1-one(32.49 g, 0.2 mol), anhydrous cesium carbonate (65.16 g, 0.2 mol), andmethyl bromide (37.5 g, 0.29 mol) (35.9 g, 83% yield). NMR spectrum isconsistent with structure. MS: APCI: M+1, 217.2 (M: 216.3).

[1018] 2.6-Hydroxy-5-(2-methylprop-2-enyl)-2,3,4-trihydronaphthalen-1-one

[1019] In a manner similar to that of Example 49, step 4, the titlecompound is prepared from6-hydroxy-5-(2-methylprop-2-enyl)-2,3,4-trihydronaphthalen-1-one (35.3g, 0.163 mol) is added to diethylaniline (100 mL) and heated to 210° C.for 18 hours. The solvent is removed in vacuo, and the residue is takenup in ethyl ether, washed with 1N HCl and then brine, and dried overanhydrous magnesium sulfate. The mixture is filtered and evaporated to asolid that is recrystallized from a mixture of tetrahydrofuran and ethylether, filtered, and dried in vacuo giving the product as a solid (4.81g, 14% yield). NMR spectrum is consistent with structure. MS: APCI: M+1,217.2 (M: 216.3).

[1020] 3.(±)-6-(2-Imidazolyl-1-phenylethoxy)-5-(2-methylprop-2-enyl)-2,3,4-trihydronaphthalen-1-one

[1021] To tetrahydrofuran (35 mL) is added6-hydroxy-5-(2-methyl-allyl)-3,4-dihydro-2H-naphthalen-1-one (1.16 g,5.38 mmol), (±) 2-imidazol-1-yl-1-phenylethanol (1.11 g, 5.92 mmol), andtriphenylphosphine (2.12 g, 8.08 mmol). A solution ofdiethylazodicarboxylate (1.4 g, 8.08 mmol) in tetrahydrofuran (20 mL) isadded over 1 hour. After stirring for 2 hours at 25° C., the mixture isevaporated in vacuo, and the residue is suspended in ethyl ether and 1Ncitric acid, washed exhaustively with ethyl ether, and the pH adjustedto 14 with 6N NaOH. The aqueous phase is extracted with ethyl ether,which is separated, washed with brine, dried over anhydrous magnesiumsulfate, and filtered. The filtrate is evaporated to a solid that ispurified by chromatography on 100 g silica gel eluted with a mixture ofchloroform/ethyl acetate (80:20). The product (Compound 52) is recoveredas a foam (0.80 g, 38% yield).

[1022] Calcd. for C₂₅H₂₆N₂O₂, 0.025 CHCl₃, 0.2H₂O: Theory: C 76.46, H6.78, N 7.13, CHCl₃ 0.81, H₂O 0.92. Found: C 76.30, H 6.93, N 7.11,CHCl₃ 0.57, H₂O 0.99.

EXAMPLE 53

[1023] Synthesis of(6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-propyl-2,3,4-trihydronaphthalen-1-one(Compound 53)

[1024] To tetrahydrofuran (50 mL, degassed) is added Wilkinsons'scatalyst (0.145 g, unreduced, Lancaster Synthesis, Inc.) followed bycompound 51 (0.4 g, 1.07 mmol). The mixture is pressurized to 49 psiwith hydrogen gas for 16 hours, after which the theoretical uptake ofhydrogen gas is observed. The mixture is filtered, evaporated in vacuo,and the residue is purified by chromatography on silica gel eluted withchloroform/1% methanol. The product (Compound 53) is obtained as a glassfrom ethyl ether (0.187 g, 46% yield). MS: APCI: M+1, 375.2 (M: 374.5).

EXAMPLE 54

[1025] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-methylprop-2-enyl)-2,3,4-trihydronaphthalen-1-one(Compound 54)

[1026] To tetrahydrofuran (35 mL) is added the product from Example 52,step 2 (0.81 g, 3.74 mmol), (R)-2-imidazol-1-yl-1-phenylethanol (0.77 g,4.11 mmol) and triphenylphosphine (1.47 g, 5.61 mmol). A solution ofdiethylazodi-carboxylate (0.98 g, 5.61 mmol) in tetrahydrofuran (15 mL)is added over 1 hour. After stirring for 18 hours at 25° C., the mixtureis evaporated in vacuo, and the residue is suspended in ethyl ether and1N citric acid, washed exhaustively with ethyl ether and the pH adjustedto 12 with 2N NaOH. The aqueous phase is extracted with a mixture ofethyl acetate and ethyl ether, which is separated, washed with brine,dried over anhydrous magnesium sulfate, and filtered. The filtrate isevaporated to a glass that is purified by chromatography on 50 g silicagel eluted with a mixture of chloroform/3% methanol. The product(Compound 54) is recovered as a foam (0.41 g, 29% yield). NMR spectrumis consistent with structure.

[1027] Calcd. for C₂₅H₂₆N₂O₂, 0.03 CHCl₃, 0.025H₂O: Theory: C 76.98, H6.73, N 7.17, CHCl₃ 0.82, H₂O 1.16. Found: C 76.58, H 6.84, N 7.13,CHCl₃ 0.89, H₂O 0.89.

EXAMPLE 55

[1028] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-methylpropyl)-2,3,4-trihydronaphthalen-1-one(Compound 55)

[1029] 1. 6-Hydroxy-5-(2-methylpropyl)-2,3,4-trihydronaphthalen-1-one

[1030] To tetrahydrofuran (100 mL) is added 5% palladium/BaSO₄ catalyst(0.2 g) followed by the product from Example 52, step 2 (2.13 g, 9.83mmol). The mixture is pressurized to 49 psi with hydrogen gas for 5hours, after which the theoretical uptake of hydrogen gas had beenachieved. The mixture is filtered, evaporated in vacuo to a solid, andthe residue is purified by recrystallization from a mixture ofdichloromethane and pentane. The product is obtained as a solid (1.95 g,91% yield). MS: APCI: M+1, 219.3 (M: 218.3). NMR spectrum is consistentwith structure.

[1031] 2.6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-methylpropyl)-2,3,4-trihydronaphthalen-1-one

[1032] To tetrahydrofuran (50 mL) is added the product from step 1 (1.8g, 8.25 mmol), (R)-2-imidazol-1-yl-1-phenylethanol (1.78 g, 9.46 mmol),and triphenylphosphine (4.4 g, 16.8 mmol). A solution ofdiethylazodicarboxylate (2.15 g, 12.3 mmol) in tetrahydrofuran (25 mL)is added over 3 hours. After stirring for 18 hours at 25° C., themixture is evaporated in vacuo, and the residue is suspended in ethylether and 1N citric acid, washed exhaustively with ethyl ether, and thepH adjusted to 13 with 2N NaOH. The aqueous phase is extracted withethyl ether, which is separated, washed with brine, dried over anhydrousmagnesium sulfate, and filtered. The filtrate is evaporated to a glassthat is purified by chromatography on 150 g silica gel eluted with agradient of chloroform to 2% methanol. The product (Compound 55) isrecovered as a foam (1.52 g, 48% yield). NMR spectrum is consistent withstructure. MS: APCI: M+1, 389.2 (M: 388.5).

[1033] Calcd. for C₂₅H₂₈N₂O₂, 0.1 CHCl₃, 0.25H₂O: Theory: C 74.45, H7.12, N 6.92, CHCl₃ 2.63, H₂O 1.11. Found: C 74.24, H 7.06, N 6.87,CHCl₃ 2.70, H₂O 1.04.

EXAMPLE 56

[1034] Synthesis of5-((1S)-2-imidazolyl-1-phenylethoxy)-4-prop-2-enylindan-1-one (Compound56)

[1035] 1. 5-Allyloxy-indan-1-one

[1036] 5-Hydroxy-indan-1-one, prepared per R. W. Hartmann, et. al., J.Med. Chem., 1994;37:1275, (14.6 g, 0.099 mol) and cesium carbonate (24.1g, 0.074 mol) are added to dimethylformamide (55 mL). Allyl bromide(9.39 mL, 0.108 mol) is added dropwise over 10 minutes, and the mixtureis heated to 80° C. for 2 hours. After stirring for 18 hours at 25° C.,the mixture is filtered, and the solvent is removed in vacuo. Theresidue is taken up into ethyl ether, washed with saturated sodiumbicarbonate solution, brine, 1N citric acid, and finally brine again.The solution is concentrated in vacuo, and a crystalline solid isobtained upon addition of hexane (14.33 g, 77% yield). NMR spectrum isconsistent with structure.

[1037] 2. 4-Allyl-5-hydroxy-indan-1-one

[1038] 5-Allyloxy-indan-1-one (12 g, 0.064 mol) is dissolved in1,2,4-trichlorobenzene (64 mL) and heated to 210° C. for 18 hours. Thesolvent is removed in vacuo, and the residue is purified by silica gelchromatography, eluted with a mixture of hexane/ethyl acetate, followedby recrystallization. A solid is recovered (1.75 g, 14.5% yield). NMRspectrum is consistent with structure.

[1039] 3. 5-((1S)-2-Imidazolyl-1-phenylethoxy)-4-prop-2-enylindan-1-one

[1040] To tetrahydrofuran (65 mL) is added 4-allyl-5-hydroxy-indan-1-one(0.8 g, 4.25 mmol), (R)-2-imidazol-1-yl-1-phenylethanol (0.88 g, 4.25mmol), and triphenylphosphine (1.67 g, 6.4 mmol). A solution ofdiethylazodicarboxylate (1.11 g, 6.4 mmol) in tetrahydrofuran (16 mL) isadded over 30 minutes. After stirring for 18 hours at 25° C., themixture is evaporated in vacuo, and the residue is suspended in ethylether and 1N citric acid, washed exhaustively with ethyl ether, and thepH adjusted to 13 with 6N NaOH. The aqueous phase is extracted withethyl ether, which is separated, washed with brine, dried over anhydrousmagnesium sulfate, and filtered. The filtrate is evaporated to a solidthat is purified by recrystallization and obtained as a solid (440 mg,29% yield). NMR spectrum is consistent with structure. MS: APCI: M+1,359.2 (M: 358.4).

[1041] Calcd. for C₂₃H₂₂N₂O₂: Theory: C 77.07, H 6.19, N 7.82. Found: C76.86, H 6.24, N 7.80.

EXAMPLE 57

[1042] Synthesis of(±)-6-(2-imidazolyl-1-(2-pyridyl)ethoxy)-5-(2-phenylethyl)-2,3,4-trihydronaphthalen-1-one(Compound 57)

[1043] 1. O-(Tetrahydro-2H-pyran-2-yl)-glycolic acid, ethyl ester

[1044] To a stirred solution of glycolic acid, ethyl ester (62.3 g,0.598 mol) and 3,4-dihydro-2H-pyran (50.30 g, 0.598 mol) indichloromethane (250 mL) at 4° C. under nitrogen is addedp-toluenesulfonic acid monohydrate (0.20 g, 0.0011 mol), and the mixtureis stirred. The temperature rises exothermically to 20° C. and is thenrecooled to 5° C. over 0.5 hour. The reaction mixture is washed withwater, dilute aqueous sodium bicarbonate, and water (2×). The organiclayer is dried (Na₂SO₄) and rotary evaporated to give 109.8 g ofO-(tetrahydro-2H-pyran-2-yl)-glycolic acid, ethyl ester as a pale yellowoil; ¹H-NMR (CDCl₃): 1.26 (t, 3H), 1.48-1.62 (m, 3H), 1.67-1.87 (m, 3H),3.50 (m, 1H), 3.84 (m, 1H), 4.19 (M, 4H), 4.72 (t, 1H) ppm.

[1045] 2. 2-Oxo-2-pyridin-2-yl-O-(tetrahydro-2H-pyran-2-yl)ethanol

[1046] To a stirred solution of 2-bromopyridine (3.70 mL, 0.039 mol) inanhydrous THF (60 mL) at −78° C. under nitrogen is added dropwise a 1.6M solution of n-butyl lithium in hexanes (22 mL, 0.035 mol) over 5minutes, and the mixture is stirred for 20 minutes. To the stirredmixture is added a solution of O-(tetrahydro-2H-pyran-2-yl)-glycolicacid, ethyl ester (7.5435 g, 0.04008 mol) in THF (20 mL) over 20minutes, and the mixture is stirred for 2 hours. The reaction isquenched by rapid dropwise addition of a saturated aqueous solution ofammonium chloride (50 mL). Ethyl ether is added and the mixture allowedto warm to 0° C. The layers are separated and the aqueous layer isextracted with ethyl ether (2×). The organics are combined, washed withbrine (3×), dried (Na₂SO₄), and rotary evaporated. The residue isdissolved in hexanes and purified by chromatography on silica gel (300g, 230-400 mesh), eluting with hexanes-ethyl acetate (4:1, 7×250 mL; 3:1, 7×250 mL) to give 4.21 g of2-oxo-2-pyridin-2-yl-O-(tetrahydro-2H-pyran-2-yl)-ethanol as a yellowoil that solidifies upon standing. Mp 63-65° C.

[1047] 3. (±)-1-Pyridin-2-yl-2-(tetrahydro-2H-pyran-2-yloxy)ethanol

[1048] To a stirred solution of2-oxo-2-pyridin-2-yl-O-(tetrahydro-2H-pyran-2-yl)ethanol (1.15 g,0.00520 mol) in methanol at 0° C. is added sodium borohydride (0.195 g,0.00515 mol) in portions. The reaction is stirred for 2.5 hours androtary evaporated to dryness. The residue is dissolved in ethyl ether,washed with brine (3×), dried (Na₂SO₄), and rotary evaporated. Theresidue is purified by chromatography on silica gel (50 g, 230400 mesh),eluting with hexanes-ethyl acetate (1:1) to give 0.84 g of(±)-1-pyridin-2-yl-2-(tetrahydro-2H-pyran-2-yloxy)-ethanol as a paleyellow oil. MS-APCI m/z 224 [M−H]⁺.

[1049] 4.(±)-6-(2-Tetrahydro-2H-1-pyran-2-yloxy-1-(2-pyridyl)ethoxy)-5-(2-phenylethyl)-2,3,4-trihydronaphthalen-1-one

[1050] To a stirred solution of6-hydroxy-5-phenethyl-2,3,4-trihydronaphthalen-1-one (0.960 g, 0.00360mmol), (±)-1-pyridin-2-yl-2-(tetrahydro-2H-pyran-2-yloxy)ethanol (0.80g, 0.0036 mol), and triphenylphosphine (0.946 g, 0.00361 mol) in THF (10mL) at 0° C. under nitrogen is added dropwise over 6 minutes DEAD (0.57mL, 0.0036 mol). The reaction is stirred for 1.6 hours and allowed towarm to room temperature overnight. The solution is rotary evaporated toreduced volume (˜3 mL), whereupon a white crystalline solid forms. Thesuspension is nearly dissolved in dichloromethane, and the mixture issubjected to chromatography on silica gel (149 g, 230-400 mesh), elutingwith hexanes-ethyl acetate (2:1). The product is rechromatographed onsilica gel (109 g), eluting with hexanes acetone (5:2) to give 0.73 g ofthe title product as an off-white foam. CHN Calc.: —C, 76.41; H, 7.05;N, 2.97; Found: C, 76.36; H, 7.21; N, 3.02.

[1051] 5.6-(2-Hydroxy-1-(2-pyridyl)ethoxy)-5-(2-phenylethyl)-2,3,4-trihydronaphthalen-1-one

[1052] To a stirred solution of the product from step 4 (0.69 g, 0.0015mol) in THF (3 mL) at room temperature is added acetic acid (9 mL) andwater (3 mL), and the solution is stirred for 3 days. The mixture isrotary evaporated in vacuo, and the residue is dissolved in toluene androtary evaporated to reduced volume until there is no odor of aceticacid. The solution is purified by chromatography on silica gel (52 g,230-400 mesh), eluting with hexanes acetone (3:2) to give 0.4126 g ofthe title compound as an off-white foam. ¹H-NMR (DMSO-d₆): 1.91 (m, 2H),2.43 (t, 2H), 2.77-3.04 (m, 6H), 3.90 (m, 2H), 5.15 (t, 1H), 5.43 (t,1H), 6.75 (d, 1H), 7.19 (m, 1H), 7.27 (m, 5H), 7.35 (d, 1H), 7.64 (d,1H), 7.75 (dt, 1H), 8.57 (dd, 1H) ppm.

[1053] 6.(±)-6-(2-Imidazolyl-1-(2-pyridyl)ethoxy)-5-(2-phenylethyl)-2,3,4-trihydronaphthalen-1-one

[1054] To a stirred solution of the product from step 5 (0.3428 g,0.0008846 mol) and pyridine (0.080 mL, 0.00099 mol) in dichloromethane(10 mL) at room temperature under nitrogen is added imidazole (0.075 g,0.00110 mol), and the resulting suspension is cooled to −78° C. To thismixture is added dropwise trifluoromethanesulfonic anhydride (0.170 mL,0.00101 mol) over 1 minute, and the mixture is stirred 30 minutes beforeallowing it to warm overnight to room temperature. The suspension isrotary evaporated, and the residue dissolved in THF.

[1055] In a separate flask, a 60% dispersion of sodium hydride inmineral oil (0.0499 g, 0.0013 mol) is added to a solution of imidazole(0.0893 g, 0.00131 mol) in THF (3 mL) at 15° C., and the mixture isstirred 10 minutes and added to the reaction mixture in THF. After 17hours, the reaction is heated at 60° C. for 1 hour, cooled, and rotaryevaporated. The residue is purified by chromatography on silica gel (41g, 230-400 mesh), eluting with dichloromethane-methanol (19:1) to give0.2390 g of a mixture of recovered starting material and a small amountof desired final product.

[1056] To a stirred solution of the mixture of this starting materialand final product (0.2000 g, 0.000516 mol), imidazole (0.0350 g,0.000514 mol), triphenylphosphine (0.1366 g, 0.000521 mol) in THF at 5°C. under nitrogen is added DEAD (0.081 mL, 0.00051 mol) dropwise over 1minute, and after 10 minutes the mixture is allowed to warm roomtemperature. After 18 hours, trifluoroacetic acid (0.15 ML, 0.0019 mol)is added, and the mixture is stirred for 4 days for convenience.Additional triphenylphosphine (0.1350 g, 0.000515 mol), imidazole(0.1480 g, 0.00217 mol) and THF (1.5 mL) are added followed by DEAD(0.085 mL, 0.00054 mol), and the mixture stirred overnight. By TLC onsilica gel, eluting with dichloromethane-methanol (10:1), no significantreaction had taken place. Therefore, the mixture is rotary evaporated,and the residue is partitioned between ethyl acetate and water. Theorganics are washed with brine, dried (Na₂SO₄), and rotary evaporated.The residue is purified by chromatography on silica gel (28 g, 230-400mesh), eluting with dichloromethane-methanol (25:1) to give 0.0070 g offinal product (Compound 57) as an off-white glass; ¹H-NMR (CDCl₃): 2.00(m, 2H), 2.53 (m, 2H), 2.76 (m, 2H), 2.90 (m, 2H), 3.11 (m, 2H), 4.53(m, 2H), 5.60 (t, 1H), 6.52 (d, 1H), 6.82 (s, 1H), 6.88 (d, 1H), 6.96(s, 1H), 7.18 (d, 2H), 7.22-7.33 (m, 5H), 7.55 (m, 1H), 7.80 (d, 1H),8.66 (d, 1H) ppm.

EXAMPLE 58

[1057] Synthesis of(±)-6-(2-Imidazolyl-1-(3-pyridyl)ethoxy)-5-(2-phenylethyl)-2,3,4-trihydronaphthalen-1-one(Compound 58)

[1058] A procedure is employed similar to that described for Example 57,steps 2-6, using 3-bromopyridine (3.70 mL, 0.038 mol). The final productis rotary evaporated, and the residue is purified by chromatography onsilica gel (15 g), eluting with CH₂Cl₂-MeOH (25:1, 20×15 mL; 20:1, 15×15mL) to give a glaze. The glaze is stirred in Et₂O until white solidsformed, and the mixture is rotary evaporated and dried in vacuo to give0.0107 g of the final product (Compound 58); ¹H-(DMSO-d₆): 1.89 (m, 2H),2.41 (m, 2H), 2.71-2.79 (m, 4H), 2.94 (m, 2H), 4.54 (dd, 1H), 4.67 (dd,1H), 5.98 (m 1H), 6.80 (d, 1H), 6.83 (s, 1H), 7.16-7.39 (m, 7H),7.57-7.72 (m, 3H), 8.50 (d, 1H), 8.62 (s, 1H) ppm.

EXAMPLE 58a

[1059]

[1060] Synthesis of6-[2-(1H-Imidazol-1-yl)-1,1-dimethylethoxy]-5-(2-phenylethyl)-3,4-dihydro-1(2H)-naphthalenone(Compound 58a)

[1061] 1. Ethyl2-methyl-2-{[5-oxo-1-(2-phenylethyl)-5,6,7,8-tetrahydro-2-naphthalenyl]oxy}propanoate

[1062] A mixture of6-hydroxy-5-(2-phenylethyl)-3,4-dihydro-1(2H)-naphthalenone (2.00 g, 7.5mmol), potassium carbonate (2.08 g, 15.0 mmol), and acetonitrile (15 mL)was heated to reflux, whereupon ethyl 2-bromo-2-methylpropanoate (1.2mL, 8.3 mmol) was added. The mixture was stirred at reflux for 2.5 h,whereupon further potassium carbonate (1.04 g, 7.5 mmol) and ethyl2-bromo-2-methylpropanoate (1.2 mL, 8.3 mmol) were added. The mixturewas stirred at reflux for a further 22 h and was then filtered andconcentrated. The residue was purified by dry-flash columnchromatography (SiO₂, 5-30% ethyl acetate-hexane) to give ethyl2-methyl-2-{[5-oxo-1-(2-phenylethyl)-5,6,7,8-tetrahydro-2-naphthalenyl]oxy}propanoateas a pale yellow oil, 2.75 g, 96% yield. NMR spectrum was consistentwith structure. MS EI: M^(+•) 380.1985 (M^(+•) 380.1988).

[1063] 2.6-(2-Hydroxy-1,1-dimethylethoxy)-5-(2-phenylethyl)-1,2,3,4-tetrahydro-1-naphthalenol

[1064] A solution of ethyl2-methyl-2-{[5-oxo-1-(2-phenylethyl)-5,6,7,8-tetrahydro-2-naphthalenyl]oxy}propanoate(1.00 g, 2.62 mmol) in tetrahydrofuran (4 mL) was added to an ice-cooledsuspension of lithium aluminum hydride (150 mg, 3.94 mmol) intetrahydrofuran (1 mL) the mixture was stirred at room temperature for 1h, and was then cooled in ice and treated sequentially with water (0.15mL), 15% aqueous sodium hydroxide (0.15 mL) and water (0.45 mL). Themixture was stirred at room temperature for 10 min, and was then dilutedwith ether (5 mL) and filtered. The filtrate was concentrated to give6-(2-hydroxy-1,1-dimethylethoxy)-5-(2-phenylethyl)-1,2,3,4-tetrahydro-1-naphthalenolas a white solid, 0.856 g, 95% yield. NMR spectrum was consistent withstructure. Calcd. for C₂₂H₂₈O₃: Theory: C, 77.61; H, 8.29. Found: C,77.42; H, 8.34.

[1065] 3.6-(2-Hydroxy-1,1-dimethylethoxy)-5-(2-phenylethyl)-3,4-dihydro-1(2H)naphthalenone

[1066] A mixture of6-(2-hydroxy-1,1-dimethylethoxy)-5-(2-phenylethyl)-1,2,3,4-tetrahydro-1-naphthalenol(0.756 g, 2.22 mmol), tetrahydrofuran (5 mL), and manganese dioxide (4.6g) was stirred for 4 h. The mixture was filtered through Celite and thefilter cake was washed thoroughly with dichloromethane. The combinedfiltrates were concentrated to give6-(2-hydroxy-1,1-dimethylethoxy)-5-(2-phenylethyl)-3,4-dihydro-1(2H)-naphthalenoneas a pale yellow solid, 0.656 g, 87% yield. NMR spectrum was consistentwith structure. Calcd. for C₂₂H₂₆O₃: Theory: C, 78.08; H, 7.74. Found:C, 77.90; H, 7.75.

[1067] 4.2-Methyl-2-{[5-oxo-1-(2-phenylethyl)-5,6,7,8-tetrahydro-2-naphthalenyl]oxy}propyltrifluoromethanesulfonate

[1068] Trifluoromethanesulfonic anhydride (0.12 mL, 0.74 mmol) was addedto a solution of pyridine (0.14 mL, 1.77 mmol) in dichloromethane (0.5mL). The resulting mixture was added over 15 min to an ice-cooledsolution of6-(2-hydroxy-1,1-dimethylethoxy)-5-(2-phenylethyl)-3,4-dihydro-1(2H)-naphthalenone(100 mg, 0.30 mmol) in dichloromethane (0.5 mL). The resulting mixturewas stirred for 15 min and was then quenched by the addition of water (2mL). The mixture was diluted with 1 M aqueous hydrochloric acid (10 mL)and extracted with ethyl acetate (3×5 mL). The combined extracts werewashed with 1 M aqueous hydrochloric acid (10 mL), saturated aqueouscopper sulfate (3×5 mL), and was then dried (brine, Na₂SO₄) andconcentrated. The residue was purified by dry-flash columnchromatography (SiO₂, 5-40% ethyl acetate-hexane) to give2-methyl-2-{[5-oxo-1-(2-phenylethyl)-5,6,7,8-tetrahydro-2-naphthalenyl]oxy}propyltrifluoromethanesulfonate as a colorless oil, 125 mg, 90% yield. NMRspectrum was consistent with structure. MS EI: M^(+•) 470.1376 (M^(+•)470.1375).

[1069] 5.6-[2-(1H-Imidazol-1-yl)-1,1-dimethylethoxy]-5-(2-phenylethyl)-3,4-dihydro-1-(2H)-naphthalenone

[1070] A mixture of sodium hydride (60% dispersion in oil, 32 mg, 0.81mmol), acetonitrile (0.4 mL), and imidazole (275 mg, 4.0 mmol) wasstirred at room temperature for 10 min, whereupon a solution of2-methyl-2-{[5-oxo-1-(2-phenylethyl)-5,6,7,8-tetrahydro-2-naphthalenyl]oxy}propyltrifluoromethane-sulfonate (190 mg, 0.40 mmol) in acetonitrile (0.8 mL)was added. The resulting mixture was stirred at reflux for 20 min andwas then concentrated. The residue was purified by dry-flash columnchromatography (SiO₂, 1-10% 2-propanol-dichloromethane) to give6-[2-(1H-imidazol-1-yl)-1,1-dimethylethoxy]-5-(2-phenylethyl)-3,4-dihydro-1(2H)-naphthalenoneas a colorless oil, 126 mg, 92% yield. NMR spectrum was consistent withstructure. MS EI: M^(+•) 388.2149 (M^(+•) 388.2151).

EXAMPLE 59

[1071] Synthesis of(±)-6-[1-(2-Chlorophenyl)-2-imidazolylethoxy]-5-prop-2-enyl-2,3,4-trihydronaphthalen-1-one(Compound 59)

[1072] 1. 2-Bromo-1-(2-chlorophenyl)ethan-1-one

[1073] To a stirred solution of o-chloroacetophenone (6.44 mL, 50 mmol)in benzene (100 mL) is added dropwise bromine (2.55 mL, 50 mmol). Thereaction is stirred under nitrogen, at room temperature, overnight. Thereaction mixture is washed three times with 2 M NaCO₃, dried over MgSO₄,and concentrated to give a clear oil (9.79 g, 84% yield). MS-APCI:M+1=234.5.

[1074] 2. 2-Bromo-1-(2-chlorophenyl)ethan-1-ol

[1075] To a solution of the product from step 1 (9.79 g, 41.9 mmol) inmethanol (100 mL) is added NaBH₄ (1.59 g, 43 mmol) in four equalportions over 15 minutes. The reaction is stirred overnight undernitrogen. The solution is concentrated and the residue taken up in ethylether. The organics are washed once with 1N acetic acid and then brine,dried over MgSO₄, filtered, and concentrated to give a clear oil (7.31g, 74% yield). MS-APCI: M+1=235.4.

[1076] 3. 1-(2-Chlorophenyl)-2-imidazolylethan-1-ol

[1077] To a suspension of NaH (60% in mineral oil) (1.36 g, 35 mmol) intetrahydrofuran (100 mL) is added a solution of imidazole (2.32 g, 34mmol) in tetrahydrofuran (10 mL). The suspension is stirred at 45° C.for 1 hour. The reaction mixture is allowed to cool to room temperatureand a solution of the compound from step 2 (7.31 g, 31 mmol) intetrahydrofuran (20 mL) is added. After the reaction mixture is refluxedovernight, the solvent is concentrated in vacuo and 100 mL of 1N citricacid is added. The aqueous layer is extracted with ethyl ether (3×50 mL)and the pH is adjusted to 10 with 25% NaOH. The aqueous layer isextracted with ethyl acetate (3×50 mL). The organic layers are combined,washed with brine, dried over MgSO₄, filtered, and concentrated to givea golden foam. Recrystalization with hot chloroform/methanol (70:30)gives the product as a golden foam (2.6 g, 38% yield). MS-APCI:M+1=223.1.

[1078] 4.(±)-6-[1-(2-Chlorophenyl)-2-imidazolylethoxy]-5-prop-2-enyl-2,3,4-trihydronaphthalen-1-one

[1079] To a solution of6-hydroxy-5-prop-2-enyl-2,3,4-trihydronaphthalen-1-one (Example 49, step4) (0.9 g, 4.45 mmol) in dry tetrahydrofuran (25 mL) is added thecompound from step 3 (1.1 g, 4.9 mmol) and triphenylphosphine (1.28 g,4.9 mmol). The reaction mixture is cooled to 0° C. and treated with asolution of diethyl azodicarboxylate (1 mL, 6.9 mmol) in tetrahydrofuran(5 mL) dropwise. The reaction is warmed to room temperature and stirredovernight. The solution is concentrated and the residue is taken up in100 mL ethyl acetate. The organic layer is washed with water (3×50 mL)and brine (2×50 mL). The solvent is removed in vacuo and 50 mL of ethylether is added. The precipitate is filtered and the ether is removed.More ethyl ether is added and the above procedure is repeated two moretimes. One hundred milliliters of ethyl acetate is added, and thesolution is dried over MgSO₄, filtered, and concentrated to give a lighttan foam. Purification is carried out via reversed-phase HPLC (0.1%trifluoroacetic acid in acetonitrile and 0.1% aqueous trifluoroaceticacid as eluent; C-18 column) to give a white solid as the final product(Compound 59); 0.348 g (15% yield). MS-APCI: M+1=407.2.

[1080] Analysis calculated for C₂₄H₂₃N₂O₂Cl₁.1.32 C₂H₁₂F₃.0.75H₂O:Theory: C, 56.49; H, 4.51; N, 4.95. Found: C, 56.50; H, 4.50; N, 4.90.

EXAMPLE 60

[1081] Synthesis of(±)-6-[0-(2,6-Dichlorophenyl)-2-imidazolylethoxy]-5-prop-2-enyl-2,3,4-trihydronaphthalen-1-one,Trifluoroacetic Acid (Compound 60)

[1082] The compound is prepared according to the procedure outlined forExample 59, steps 14, using 2,6-dichloroacetophenone. Purification iscarried out via reversed-phase HPLC (0.1% trifluoroacetic acid inacetonitrile and 0.1% aqueous trifluoroacetic acid as eluent; C-18column) to give a white solid (Compound 60) (0.012 g, 1.5% yield).MS-APCI: M+1=441.1.

[1083] Analysis calculated for C₂₄H₂₂N₂O₂Cl₂ 1.37 C₂H₁O₂F₃.0.88H₂O:Theory: C, 52.68; H, 4.30; N, 6.10. Found: C, 52.70; H, 4.30; N, 6.10.

EXAMPLE 61

[1084] Synthesis of(±)-6-(2-imidazolyl-1-(2-thienyl)ethoxy)-5-prop-2-ethyl-2,3,4-trihydronaphthalen-1-one(Compound 61)

[1085] 1. 2-Bromo-1-(2-thienyl)ethan-1-one

[1086] To a stirred solution of 2-acetylthiophene (5.38 mL, 50 mmol) inbenzene (100 mL) is added dropwise bromine (2.55 mL, 50 mmol). Thereaction is stirred under nitrogen at room temperature overnight. Thereaction mixture is washed three times with 2 M Na₂CO₃, dried overMgSO₄, and concentrated to give a brown oil (8.0 g, 78% yield). MS-APCI:M+1=206.0.

[1087] 2. 2-Bromo-1-(2-thienyl)ethan-1-ol

[1088] To a solution of the product from step 1 (7.7 g, 37.5 mmol) inmethanol (100 mL) is added NaBH₄ (1.59 g, 43 mmol) in four equalportions over 15 minutes. The reaction is stirred overnight undernitrogen. The solution is concentrated and the residue taken up in ethylether. The organics are washed once with 1N acetic acid and then brine,dried over MgSO₄, filtered, and concentrated to give a clear oil (4.9 g,64% yield). MS-APCI: M+1=207.0.

[1089] 3. 2-Imidazolyl-1-(2-thienyl)ethan-1-ol

[1090] To a suspension of NaH (60% in mineral oil) (1.15 g, 48 mmol) intetrahydrofuran (100 mL) is added a solution of imidazole (1.64 g, 24mmol) in tetrahydrofuran (10 mL). The suspension is stirred at 45° C.for 1 hour. The reaction mixture is allowed to cool to room temperatureand a solution of the compound from step 2 (4.9 g, 24 mmol) intetrahydrofuran (20 mL) is added. After the reaction mixture is refluxedovernight, the solvent is concentrated in vacuo, and 100 mL of 1N citricacid is added. The aqueous layer is extracted with ethyl ether (3×50 mL)and the pH is adjusted to 10 with 25% NaOH. The aqueous layer isextracted with ethyl acetate (3×50 m]L). The organic layers arecombined, washed with brine, dried over MgSO₄, filtered, andconcentrated to give a golden foam. Recrystalization with hotchloroform/methanol (70:30) gives the product as a golden foam (1.0 g,21% yield). MS-APCI: M+1=195.0.

[1091] 4.6-(2-Imidazolyl-1-(2-thienyl)ethoxy)-5-prop-2-enyl-2,3,4-trihydronaphthalen-1-one

[1092] To a solution of6-hydroxy-5-prop-2-enyl-2,3,4-trihydronaphthalen-1-one (Example 49, step4) (0.285 g, 1.4 mmol) in dry tetrahydrofuran (15 mL) is added thecompound from step 3 (0.300 g, 1.55 mmol) and triphenylphosphine (0.259g, 1.55 mmol). The reaction mixture is cooled to 0° C. and treated witha solution of diethyl azodicarboxylate (0.25 mL, 1.7 mmol) intetrahydrofuran (5 mL) dropwise. The reaction is warmed to roomtemperature and stirred overnight. The solution is concentrated, and theresidue is taken up in 50 mL ethyl acetate. The organic layer is washedwith water (3×25 mL) and brine (2×25 mL). The solvent is removed invacuo, and 25 mL of ethyl ether is added. The precipitate is filtered,and the ether is removed. More ethyl ether is added and the aboveprocedure is repeated two more times. Fifty milliliters of ethyl acetateis added and the solution is dried over MgSO₄, filtered and concentratedto give a light tan foam. Purification is carried out via reversed-phaseHPLC (0.1% trifluoroacetic acid in acetonitrile and 0.1% aqueoustrifluoroacetic acid as eluent; C-18 column) to give a golden solid asthe final product (Compound 61) (0.039 g, 7.5% yield). MS-APCI:M+1=379.0.

[1093] Analysis calculated for C₂₂H₂₂N₂O₂S₁1.14H₂O:

[1094] Theory: C, 63.50; H, 5.61; N, 6.73.

[1095] Found: C, 63.40; H, 5.50; N, 7.50.

EXAMPLE 62

[1096] Synthesis of6-((1S)-2-imidazolyl-1-phenylethylthio)-5-propyl-2,3,4-trihydronaphthalen-1-one(Compound 62)

[1097] 1. 6-Hydroxy-5-propyl-2,3,4-trihydronaphthalen-1-one

[1098] A solution of 4.41 g (21.8 mmol) of 5-allyl-6-hydroxy-1-tetralonein 100 mL THF is treated with 0.4 g 20% Pd/BaSO₄ and reduced at 25°C./50 psi H₂. The mixture is filtered and the solvent removed underreduced pressure to give 4.45 g (100% yield) of the product as a whitesolid. The structure is confirmed by NMR and mass spectroscopy.

[1099] 2.6-[(Dimethylamino)thioxomethoxy]-5-propyl-2,3,4-trihydronaphthalen-1-one

[1100] A solution of 5.14 g (25.2 mmol) of the product from step 1 in 50mL DMF is treated with 8.2 g (25.2 mmol) of CsCO₃ and warmed to 85° C.for 0.5 hour. The mixture is then treated dropwise rapidly with asolution of 3.9 g (31 mmol) of N,N-dimethylthiocarbamoyl chloride in 10mL DMF. After stirring at room temperature for 0.5 hour, the mixture isheated at 85° C. for 0.5 hour. The mixture is poured into H₂O andextracted twice with EtOAc. The EtOAc layer is washed twice with 5%NaOH, then H₂O, and sat. NaCl. Drying over MgSO₄ and removal of thesolvent under reduced pressure leaves the crude product. Chromatographyon silica gel, eluting with CH₂Cl₂ affords 3.68 g (50.2% yield) of theproduct as an oil. The structure is confirmed by NMR and massspectroscopy.

[1101] 3.N,N-Dimethyl(5-oxo-1-propyl(2-6,7,8-trihydronaphthylthio))-carboxamide

[1102] A flask containing 3.56 g (12.2 mmol) of the thiocarbamate fromstep 2 is heated at 240° C. for 1 hour. The material is taken up inCHCl₃ and washed with sat. NaCl. Drying over MgSO₄ and removal of thesolvent under reduced pressure leaves the crude product. Chromatographyon silica gel, eluting with CHCl₃/EtOAc (96:4) gives 2.07 g (58.2%yield) of the product as a golden solid. Mp 124-126° C. The structure isconfirmed by NMR and mass spectroscopy.

[1103] 4. 5-Propyl-6-sulfanyl-2,3,4-trihydronaphthalen-1-one

[1104] A solution of 2.07 g (7.1 mmol) of the rearranged product fromstep 3 in 10 mL MeOH is treated with a solution of 1.0 g (25 mmol) ofNaOH in 35 mL MeOH and heated at reflux for 1.5 hour. The solution isacidified with conc. HCl, diluted with H₂O, and extracted twice withCHCl₃. The CHCl₃ is washed with sat. NaCl, dried over MgSO₄, and thesolvent removed under reduced pressure leaving 1.56 g (100% yield) ofthe product as an oil which crystallizes on standing. The structure isconfirmed by NMR and mass spectroscopy.

[1105] 5.6-((1S)-2-Imidazolyl-1-phenylethylthio)-5-propyl-2,3,4-trihydro-naphthalen-1-one

[1106] Under nitrogen, a solution of 2.24 g (8.5 mmol) oftriphenylphosphine in 20 mL THF is cooled in ice and 1.4 mL (8.5 mmol)of diethyl azodicarboxylate added slowly. After stirring at 0° C. for0.5 hour, 1.5 g (7.8 mmol) of (R)-1-phenyl-2-(1-imidazoyl)ethanol in 10mL THF is added followed by a solution of 1.56 g (7.1 mmol) of theproduct from step 4 in 5 mL THF. The reaction is allowed to stir at roomtemperature for 4 days. The mixture is diluted with Et₂O and extractedtwice with 1N HCl. The acid portion is made basic with 50% NaOH andextracted twice with CH₂Cl₂. The CH₂Cl₂ is washed with sat. NaCl, driedover MgSO₄, and the solvent removed under reduced pressure leaving thecrude product. Two chromatographies on silica gel, eluting withCH₂Cl₂/acetone (80:20) gives 0.72 g (26% yield) of the final product(Compound 62) as a white hygroscopic foam. The structure is confirmed byNMR and mass spectroscopy. Calcd for C₂₄H₂₆N₂OS.0.1CH₂Cl₂ (MW 398.96):Theory: C, 72.55 H, 6.62 N, 7.02. Found: C, 72.30 H, 6.53 N, 6.75.

EXAMPLE 63

[1107] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethylthio)-5-(2-phenylethyl)-2,3,4-trihydronaphthalen-1-one(Compound 63)

[1108] The procedures of Example 62 steps 2-5 are followed using 4.0 g(15 mmol) of 5-phenethyl-6-hydroxy-1-tetralone to give the crudeproduct. Chromatography on silica gel, eluting with CH₂Cl₂/acetone(80:20) gives 0.26 g of the final product (Compound 63) as a tan foam.

[1109] Calcd C₂₉H₂₈N₂OS.0.05CH₂Cl₂ (MW 456.78): Theory: C, 76.38 H, 6.20N, 6.13. Found: C, 76.16 H, 6.27 N, 6.26.

EXAMPLE 63a

[1110]

[1111] Synthesis of6-((S)-2-Imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-phenethyl-3,4-dihydro-2H-naphthalen-1-one(Compound 63a)

[1112] 1. 2-Bromo-1-pyridin-3-yl-ethanone

[1113] To a stirred solution of 48% hydrobromic acid was added3-acetylpyridine (24 g, 0.198 mol) with cooling to 0° C. Bromine (34.4g, 0.215 mol) was added at a dropwise rate followed by stirring at 25°C. for 1.5 hours and heating to 70° C. for 1 hour. The mixture wascooled to 0° C. and ethyl ether, 800 ml was added, giving a solidprecipitate. The solid was washed with ether and dried in vacuo giving awhite solid as the hydrobromide salt, 48.3 g, 87% yield, mp165-175° C.MS: APCI: M+1: 201.9 (M: 200.04).

[1114] 2. 2-Bromo-1-pyridin-3-yl-ethanol

[1115] To a stirred suspension of sodium borohydride (5.29 g, 0.14 mol)in methanol (300 ml) was added a suspension of2-Bromo-1-pyridin-3-yl-ethanone (10 g, 0.035 mol) in methanol (200 mL)at −40° C. over 30 minutes, allowing temperature to reach −35° C. Themixture was warmed to 5° C. over 30 minutes followed by cooling to −60°C. for 1 hour. The methanol was stripped from the mixture in vacuo whilecold, followed by trituration with ethyl acetate. The ethyl acetate wasdecanted and washed with a minimal amount of saturated sodiumbicarbonate solution, washed with brine, dried over anhydrous magnesiumsulfate and filtered. The filtrate was evaporated to a red oil, 6.92 g,98% yield, MS: APCI: M+1: 203.9 (M: 202.06). Material appeared to beunstable at 25° C. and was used immediately in the following step.

[1116] 3. 3-Oxiranyl-pyridine

[1117] To a stirred suspension of sodium hydride (2.3 g, 0.035 mol) intetrahydrofuran (100 ml) was added a solution of2-Bromo-1-pyridin-3-yl-ethanol (7 g, 0.035 mol) over 15 minutes whilemaintaining temperature at 5° C. for 1 hour. The mixture was cooled to−40° C. and allowed to warm to 25° C. over 16 hours. Solids were removedby filtration and the filtrate was evaporated to an oil. The oil wastriturated with pentane leaving behind a dark orange gum. Th decantatewas evaporated to an oil, 2.62 g, 62% yield, MS: APCI: M+1: 121.9 (M:221.14).

[1118] 4. 2-Imidazol-1-yl-1-pyridin-3-yl-ethanol

[1119] Imidazole (1.84 g, 0.027 mol) in dimethylformamide (8 ml) wasadded to 3-Oxiranyl-pyridine (2.62 g, 0.022 mol) followed by heating to100° C. for 3 hours. The solvent was removed in vacuo and the residuewas chromatographed on a Biotage 40S silica gel column eluted with agradient of 100% chloroform to 90:10 chloroform/methanol, giving asolid, 1.62 g, 38% yield, mp. 119-121° C. NMR spectroscopy confirmed theidentity of the product.

[1120] 4.6-((S)-2-Imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-phenethyl-3,4-dihydro-2H-naphthalen-1-one

[1121] In a manner similar to that of Example 20 Step4,6-Hydroxy-5-phenethyl-3,4-dihydro-2H-naphthalen-1-one (0.86 g, 3.23mmol), and 2-imidazol-1-yl-pyridinyl-ethanol gave a solid mixture of rand s isomers, 0.82 g, 58% yield. MS: APCI: M+1, 438.3 (M: 437.6).

[1122] The rs isomer mixture thus obtained was separated by chiralchromatography using a 5μ Chiralpak AS column (Daicel ChemicalIndustries) 25×4.5 cm eluted at 11.0 ml/min with a mixture of hexanesand isopropanol. The fractions observed at 275 nm corresponding to thesecond eluted isomer at 17.06 minutes retention time were collected andevaporated to a solid, 0.354 g, 12.8% yield, MS: APCI: M+1: 438.2 (M:437.55).

[1123] Calcd. For C28H27N3O2, 0.75H2O: Theory: C, 74.56; H, 6.37; N,9.36 Found: C, 74.29; H, 6.52; N, 9.14

EXAMPLE 63b

[1124]

[1125] Synthesis of6-((S)-2-Imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-(propane-2-sulfonylmethyl)-3,4-dihydro-2H-napthalen-1-one(Compound 63b)

[1126] 1. (R)-2-Imidazol-1-yl-1-pyridin-3-yl-ethanol

[1127] The racemic mixture of 2-imidazol-1-yl-1-pyridin-3-yl-ethanolprepared per (example 63a step 4) was separated by chiral chromatographyusing a 5μ Chiralpak AS column (Daicel Chemical Industries) 25×4.5 cmeluted at 1.0 ml/min with a mixture of hexanes and isopropanol. Thefractions observed at 275 nm corresponding to the second eluted isomerat 14.6 minutes retention time were collected and evaporated to a solid,and used as is in the following reaction.

[1128] 2.6-((S)-2-Imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-(propane-2-sulfonylmethyl)-3,4-dihydro-2H-napthalen-1-one

[1129] In a manner similar to that of Example 7, step2,6-Hydroxy-5-isopropylsulfonylmethyl-3,4-dihydro-2H-naphthalen-1-one(0.19 g, 0.67 mmol) and (R)-2-Imidazol-1-yl-1-pyridin-3-yl-ethanol (0.16g, 0.80 mmol) gave 0.30 g, 100% yield of a solid foam. MS: APCI: M+1:454.1 (M: 453.6). Calcd. For C₂₄H₂₇N₃O₄S, 0.125 CHCl₃: Theory: C, 61.85;H, 5.84; N, 8.97; Cl, 2.84 Found: C, 61.65; H, 5.78; N, 10.04; Cl, 2.49

EXAMPLE 63ba

[1130]

[1131] Synthesis of6-((S)-2-Imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-(pyridin-2-ylsulfonylmethyl)-3,4-dihydro-2H-napthalen-1-one(Compound 63ba)

[1132] In a manner similar to that of Example 10,(R)-2-Imidazol-1-yl-1-pyridin-3-yl-ethanol (0.389 g, 2.02 mmol) and6-Hydroxy-5-(pyridine-2-sulfonylmethyl)-,3,4-trihydro-2H-naphthalen-1-one(0.564 g, 1.78 mmol) gave 0.174 g, 18% yield of solid. MS: APCI: M+1:489.1 (M: 488.57).

[1133] Calcd. For C26H24N4O4S, 1.1H₂O Theory: C, 61.42; H, 5.19; N,11.02, H₂O 3.89

[1134] Found: C, 61.21; H, 5.21; N, 10.89, H₂O 3.09

EXAMPLE 63c

[1135]

[1136] Synthesis of6-(S)-2-Imidazol-1-yl-1-pyridin-3-ethoxy)-5-(2-pyridin-2-yl-ethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 63c)

[1137] In a manner similar to that of Example 24,6-Hydroxy-5-(2-pyridin-2-yl-ethyl-2,3,4-trihydronaphthalen-1-one (0.15g, 0.56 mmol), and ((R)-2-Imidazol-1-yl-1-pyridin-3-yl-ethanol (0.134 g,0.627 mmol) gave a solid, 0.106 g, 43% yield. MS: APCI: M+1, 439.3 (M:438.5). Calcd. For C₂₇H₂₆N₄O₂, 0.5H₂O: Theory: C, 73.20; H, 6.03; N,12.70, H₂O 2.00 Found: C, 73.13; H, 5.94; N, 12.65, H₂O 0.27

EXAMPLE 63d

[1138]

[1139] Synthesis of Isoquinoline-1-carboxylic acid[2-((S)-2-imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide(Compound 63d)

[1140] 1.6-((S)-2-Imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-nitro-3,4-dihydro-2H-naphthalen-1-one

[1141] To a solution of 6-hydroxy-5-nitro-1-tetralone (0.957 g, 4.62mmol) in dry THF (20 mL) was added(R)-2-imidazol-1-yl-1-pyridin-3-yl-ethanol (0.875 g, 4.62 mmol) followedby triphenylphospine (1.33 g, 5.08 mmol). After approximately 10 min,diethylazodicarboxylate (0.80 mL, 5.08 mmol) was added slowly. Thereaction became homogenous. The reaction was allowed to stir at RTovernight. The reaction mixture was concentrated under reduced pressureand the residue was triturated with Et₂O to remove some of the phospineby-products. The residue was dissolved in EtOAc and washed with H₂O,saturated aqueous NaHCO₃ and brine, dried over Na₂SO₄, and concentratedto give a foam/oil. Purification by chromatography (SiO₂, 4-10%MeOH/CH₂Cl₂) afforded the title compound as a tan foam (1.66 g, 4.39mmol, 95%). The structure was confirmed by NMR and mass spectrometry. MSm/z 379 (M⁺+H).

[1142] 2.5-Amino-6-((S)-2-imidazol-1-yl-1-pyridin-3-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one

[1143] A mixture of6-((S)-2-Imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-nitro-3,4-dihydro-2H-naphthalen-1-one(1.60 g, 4.23 mmol), MeOH (85 mL), H₂O (19 mL) and glacial acetic acid(2.4 mL, 42 mmol) was treated at reflux with iron powder (2.34 g, 42mmol). The reaction was monitored by mass spectrometry and was completein 4 h. The volume of solvent was reduced under reduced pressure. EtOAcand dilute aqueous NaHCO₃ were added. A brownish-green emulsion formedwhich was filtered through Celite. The mixture was extracted with EtOAc.The combined organic layer was washed with dilute aqueous NaHCO₃ andbrine, dried over Na₂SO₄, and concentrated under reduced pressure togive an off-white foam (0.685 g, 1.97 mmol, 46%). The structure wasconfirmed by NMR and mass spectrometry. MS m/z 349 (M⁺+H).

[1144] 3. Isoquinoline-1-carboxylic acid[2-((S)-2-imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide

[1145] To a mixture of5-amino-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one(100 mg, 0.287 mmol), 1-isoquinoline carboxylic acid (60 mg, 0.344mmol), and HATU (131 mg, 0.344 mmol) was added CH₂Cl₂ (3 mL) and Et₃N(48 μL, 0.344 mmol). The reaction was stirred at RT for 5 h. The mixturewas diluted with CH₂Cl₂ and washed with H₂O, saturated aqueous NaHCO₃and brine, dried over Na₂SO₄, and concentrated to give a foam/oil.Purification by chromatography (SiO₂, 5-8% MeOH/CH₂Cl₂) afforded thetitle compound as a foam (114 mg, 0.226 mmol, 79%). The structure wasconfirmed by NMR and mass spectrometry. MS m/z 504 (M⁺+H).

EXAMPLE 63e

[1146]

[1147] Synthesis of Pyrazine-2-carboxylic acid[2-((S)-2-imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide(Compound 63e)

[1148] The procedure in Example 63d step 3 was followed using2-pyrazinecarboxylic acid. The reaction was stirred at RT for 4 h.Purification by chromatography (SiO₂, 5-10% MeOH/CH₂Cl₂) afforded thetitle compound as a foam (55 mg, 0.121 mmol, 42%). The structure wasconfirmed by NMR and mass spectrometry. MS m/z 455 (M⁺+H).

EXAMPLE 63f

[1149]

[1150] Synthesis of Cinnoline-4-carboxylic acid[2-((S)-2-imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide(Compound 63f)

[1151] The procedure in Example 63d step 3 was followed usingcinnoline-4-carboxylic acid. The reaction was stirred at RT for 1 dayand at reflux for 1 day. Purification by chromatography (SiO₂, 5-8%MeOH/CH₂Cl₂ with 1% NH₄OH) afforded the title compound as a foam (63 mg,0.125 mmol, 44%). The structure was confirmed by NMR and massspectrometry. MS m/z 505 (M⁺+H).

EXAMPLE 63g

[1152]

[1153] Synthesis of6-((S)-1-Imidazol-1-ylmethyl-2-methyl-propoxy)-5-(propane-2-sulfonylmethyl)-3,4-dihydro-2H-napthalen-1-one(Compound 63g)

[1154] 1. (R)-1-Imidazol-1-yl-3-methyl-butan-2-ol

[1155] To a solution of (R)-1,2-epoxy-3-methylbutane (6.08 g, 60 mmol,Chirex Chemical Corp.) in acetonitrile (50 ml) was added imidazole (3.41g, 50 mmol) followed by heating to 80° C. for 15 hours. The mixture wasconcentrated in vacuo and the purified by silica gel chromatographyeluted with 10% methanol: dichloromethane with 1% ammonium hydroxide,giving a waxy solid, 5.0 g, 65% yield.

[1156] 2.6-((S)-1-Imidazol-1-ylmethyl-2-methyl-propoxy)-5-(propane-2-sulfonylmethyl)-3,4-dihydro-2H-napthalen-1-one

[1157] In a manner similar to that of Example 7, step2,6-Hydroxy-5-isopropylsulfonylmethyl-3,4-dihydro-2H-naphthalen-1-one(1.02 g, 3.60 mmol) and (R)-1-Imidazol-1-yl-3-methyl-butan-2-ol (0.73 g,4.7 mmol) gave 0.5 g, 33% yield of a solid foam. MS: APCI: M+1: 419.2(M: 418.6). Calcd. For C₂₂H₃₀N₂O₄S, 0.15 CHCl₃:

[1158] Theory: C, 60.95; H, 6.96; N, 6.42; Cl, 3.65 Found: C, 60.51; H,7.02; N, 6.39; Cl, 3.32

EXAMPLE 63h

[1159]

[1160] Synthesis of Isoquinoline-1-carboxylic acid[2-((S)-1-imidazol-1-ylmethyl-2-methyl-propoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide(Compound 63h)

[1161] 1.6-((S)-1-imidazol-1-ylmethyl-2-methyl-propoxy)-5-nitro-3,4-dihydro-2H-naphthalen-1-one

[1162] To a solution of 6-hydroxy-5-nitro-1-tetralone (0.888 g, 4.29mmol) in dry THF (10 mL) was added(R)-1-imidazol-1-ylmethyl-2-methyl-propanol (0.737 g, 4.78 mmol)followed by triphenylphospine (1.26 g, 4.78 mmol). After approximately10 min, diethylazodicarboxylate (0.75 mL, 4.78 mmol) was added slowly.The reaction was allowed to stir at RT for 2 days. The reaction mixturewas concentrated under reduced pressure and the residue was purified bychromatography (SiO₂, 20% acetone/CH₂Cl₂ then 5% MeOH/CH₂Cl₂) affordedthe title compound as a foam (1.02 g, 2.97 mmol, 69%). The structure wasconfirmed by NMR and mass spectrometry. MS m/z 344 (M⁺+H).

[1163] 2.5-Amino-6-((S)-1-imidazol-1-ylmethyl-2-methyl-propoxy)-3,4-dihydro-2H-naphthalen-1-one

[1164] A mixture of6-((S)-1-imidazol-1-ylmethyl-2-methyl-propoxy)-5-nitro-3,4-dihydro-2H-naphthalen-1-one(1.02 g, 2.97 mmol), MeOH (60 ML), H₂O (15 mL) and glacial acetic acid(1.7 mL, 29 mmol) was treated at reflux with iron powder (1.62 g, 29mmol). The reaction was monitored by mass spectrometry and was completein 5 h. The volume of solvent was reduced under reduced pressure. EtOAcand dilute aqueous NaHCO₃ were added. A brownish-green emulsion formedwhich was filtered through Celite. The mixture was extracted with EtOAc.The combined organic layer was washed with dilute aqueous NaHCO₃ andbrine, dried over Na₂SO₄, and concentrated under reduced pressure.Purification by chromatography (4% MeOH/EtOAc with 1% NH₄OH) affordedthe title compound as a white foam (0.750 g, 2.39 mmol, 81%). Thestructure was confirmed by NMR and mass spectrometry. MS m/z 314 (M⁺+H).

[1165] 3. Isoquinoline-1-carboxylic acid[2-((S)-1-imidazol-1-ylmethyl-2-methyl-propoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide

[1166] To a solution of5-amino-6-((S)-1-imidazol-1-ylmethyl-2-methyl-propoxy)-3,4-dihydro-2H-naphthalen-1-one(105 mg, 0.335 mmol) and 1-isoquinoline carboxylic acid (70 mg, 0.402mmol) in DMF (3 mL) was added Et₃N (56 μL, 0.402 mmol) followed by HATU(153 mg, 0.402 mmol). The reaction was stirred at RT overnight. The DMFwas removed under reduced pressure. The residue was diluted with EtOAcand washed with H₂O, saturated aqueous NaHCO₃ and brine, dried overNa₂SO₄, and concentrated. Purification by chromatography (5% MeOH/EtOAcwith 1% NH₄OH) afforded the title compound as a foam (66 mg, 0.141 mmol,42%). The structure was confirmed by NMR and mass spectrometry. MS m/z469 (M⁺+H).

[1167] EXAMPLE 63i

[1168] Synthesis of(S)-6-(1-imidazol-1-ylmethyl-2-methyl-propoxy)-5-(2-pyridin-4-yl-ethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 63i)

[1169] The title compound was prepared using the procedure of Example24, step 4 using6-hydroxy-5-(2-pyridine-2-yl-ethyl)-3,4-dihydro-2H-naphthalen-1-one and(R)-1-Imidazol-1-ylmethyl-2-methyl-propanol.

[1170] The product was obtained as a white foam (0.13 g, 17% yield). MSAPCI 404 [M+H]⁺; anal. calcd. for C₂₅H₂₉N₃O₂.2HCL/2.61H₂O MWC=523.47 C,57.36%; H, 6.97%; N, 8.03% found C, 57.37%; H, 6.81%; N, 8.35%.

EXAMPLE 63j

[1171]

[1172] Synthesis of(S)-6-[-1-(2,4-Difluoro-phenyl)-2-imidazol-1-yl-1-ethoxy]-5-(pyridin-2-ylsulfonylmethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound ⁶³j)

[1173] 1. (R)-1-(2,4-Difluoro-phenyl)-2-Imidazol-1-yl-ethanol

[1174] Imidazole (3.27 g, 0.048 mol) was dissolved in DMF (15 mL) andheated to 100° C. Then the 2,4-difluorophenylstyrene oxide (Chirex, 5 g,0.032 mol) in 15 mL DMF was added dropwise over ½ hour. Reaction washeated at 100° C. over the weekend. Solvent removed in vacuo and EtOAcwas added. The organic layer was washed with water (2×), sat. NaHCO₃soln. (2×), and brine. Dried over MgSO₄ and solvent removed in vacuo.Recrystallized using EtOAc (20 mL) giving an off-white solid (3.4 g, 47%yield). NMR (DMSO); MS 225 [M+H]⁺; mp 117-120° C.; anal calcd. forC₁₁H₁₀F₂N₂O₁ C, 58.93%; H, 4.50%; N, 12.49% found C, 58.96%; H, 4.37%;N, 12.38%.

[1175] 2.(S)-6-[-1-(2,4-Difluoro-phenyl)-2-imidazol-1-yl-1-ethoxy]-5-(pyridin-2-ylsulfonylmethyl)-3,4-dihydro-2H-naphthalen-1-one

[1176] The title compound was prepared using the procedure of Example10, step (b) using6-Hydroxy-5-(pyridine-2-sulfonylmethyl)-3,4-dihydro-2H-naphthalen-1-oneand (R)-1-(2,4-difluoro-phenyl)-2-Imidazol-1-yl-ethanol.

[1177] Obtained white foam (0.34 g, 94% yield). NMR (DMSO); MS APCI 524[M+H]⁺; HPLC RT=14.04 min. 93.4% pure 254 nm; anal. calcd. forC₂₇H₂₃F₂N₃O₄S₁.1.48HCl//0.96H₂O MWC=594.82 C, 54.52%; H, 4.47%; N, 7.06%found C, 54.52%; H, 4.47%; N, 6.84%.

EXAMPLE 63k

[1178]

[1179] Synthesis of(S)-6-[-1-(4-Fluoro-phenyl)-2-imidazol-1-yl-1-ethoxy]-5-(2-pyridin-4-yl-ethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 63k)

[1180] 1. (R)-1-(4-Fluoro-phenyl)-2-Imidazol-1-yl-ethanol

[1181] Imidazole (7.34 g, 0.11 mol) was dissolved in DMF (25 mL) andheated to 100° C. Then the 4-fluorophenylstyrene oxide (Chirex, 10 g,0.072 mol) in DMF (25 mL) was added dropwise over ½ hour. Reaction washeated at 100° C. for 4 hours then stirred at room temperatureovernight. Filtered white solid (7.27 g, 31% yield). NMR (DMSO); MS APCI207 [M+H]⁺; mp 162-164° C.; anal. calcd. for C₁₁H₁₁F₁N₂O₁ C, 64.07%; H,5.38%; N, 13.58% found C, 63.99%; H, 5.33%; N, 13.70%.

[1182] 2.(S)-6-[-1-(4-Fluoro-phenyl)-2-imidazol-1-yl-1-ethoxy]-5-(2-pyridin-4-yl-ethyl)-3,4-dihydro-2H-naphthalen-1-one

[1183] The title compound was prepared using the procedure of Example24, step 4 using6-hydroxy-5-(2-pyridine-2-yl-ethyl)-3,4-dihydro-2H-naphthalen-1-one and(R)-1-(4-fluoro-phenyl)-2-Imidazol-1-yl-ethanol. HPLC 100% 254 nmRT=14.5 min.; MS APCI 456 [M+H]⁺, anal calcd. forC₂₈H₂₆F₁N₃O₂.2HCl/2.19H₂O MWC=567.91 C, 59.22%; H, 5.75%; N, 7.40% foundC, 59.22%; H, 5.48%; N, 7.57%.

EXAMPLE 631

[1184]

[1185] Synthesis of6-[1-(1H-Imidazol-1-ylmethyl)-2-methylpropoxy]-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone(Compound 63l)

[1186] 1. 2-Isopropyloxirane

[1187] 3-Methyl-1-butene (6.25 g, 89 mmol) was passed into an ice-cooledsuspension of m-chloroperoxybenzoic acid (15.0 g, 70%, 61 mmol) ino-dichlorobenzene (45 mL). The mixture was stirred at room temperaturefor 17 h, and was then filtered. The filtrate was washed with saturatedaqueous Na₂S₂O₅ (2×10 mL), saturated aqueous NaHCO₃. (2×10 mL), anddried (brine, Na₂SO₄, KOH). The mixture was distilled to give2-isopropyloxirane (2.38 g, 46%) as a colorless liquid. NMR spectrum wasconsistent with structure.

[1188] 2. 1-(1H-Imidazol-1-yl)-3-methyl-2-butanol

[1189] A solution of 2-isopropyloxirane (2.28 g, 26 mmol) and imidazole(1.80 g, 26 mmol) in acetonitrile (25 mL) was stirred at reflux for 16h. The mixture was concentrated, and the residue was purified by flashcolumn chromatography (SiO₂, CH₂Cl₂-methanol-ammonium hydroxide 80:20:1)to give 1-(1H-imidazol-1-yl)-3-methyl-2-butanol as a yellow oil, 1.88 g,46% yield. NMR spectrum was consistent with structure. MS EI: M^(+•)154.1103 (M^(+•) −154.1106).

[1190] 4.6-hydroxy-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone

[1191] A mixture of5-(chloromethyl)-6-hydroxy-3,4-dihydro-1(2H)-naphthalenone (10.0 g, 48mmol), sodium phenylsulfinate (23.4 g, 142 mmol) and acetonitrile (100mL) was stirred at reflux under nitrogen overnight. The mixture waspoured onto ice. The precipitate was isolated by filtration, air dried,and crystallized from methanol-dichloromethane-ethyl acetate to give6-hydroxy-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone asa cream solid, 12.16 g, 84% yield. NMR spectrum was consistent withstructure.

[1192] 5.6-[1-(1H-Imidazol-1-ylmethyl)-2-methylpropoxy]-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone

[1193] Diethyl azodicarboxylate (0.16 mL, 0.99 mmol) was added over 10min to a mixture of6-Hydroxy-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2h)-naphthalenone(300 mg, 0.99 mmol), 1-(1H-imidazol-1-yl)-3-methyl-2-butanol (167 mg,1.08 mmol), triphenylphosphine (259 mg, 0.99 mmol) and tetrahydrofuran(2 mL) under nitrogen. The resulting mixture was stirred for 3 d,whereupon it was concentrated and the residue was purified by dry-flashcolumn chromatography (SiO₂, 1-9% 2-propanol-dichloromethane) to give6-[1-(1H-imidazol-1-ylmethyl)-2-methylpropoxy]-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone as a colorless solid, 46 mg, 10% yield. NMR spectrumwas consistent with structure. Calcd. for C₂₅H₂₈N₂O₄S.¼H₂O: Theory: C,65.69; H, 6.28; N, 6.13. Found: C, 65.77; H, 6.67; N, 6.11.

EXAMPLE 63m

[1194] Synthesis of6-{[1-(1H-Imidazol-ylmethyl)pentyl]oxy}-5-[(phenylsulfonyl)methyl-1-3,4-dihydro-1(2H)-naphthalenone(Compound 63 nm)

[1195] 1. 1-(1H-Imidazol-1-yl)-2-hexanol

[1196] A solution of 1,2-epoxyhexane (2.0 mL, 17 mmol) and imidazole(1.08 g, 16 mmol) in acetonitrile (14 mL) was stirred at reflux for 19h. The mixture was concentrated, taken up in 2.5 M aqueous hydrochloricacid (15 mL), washed with ethyl acetate (3×6 mL), basified with sodiumcarbonate and extracted with ethyl acetate (3×6 mL). The combinedextracts were dried (Na₂SO₄) and concentrated. The residue was purifiedby flash column chromatography (SiO₂, CH₂Cl₂-methanol-ammonium hydroxide80:20:1) to give 1-(1H-imidazol-1-yl)-2-hexanol as a colorless oil, 1.68g, 63% yield. NMR spectrum was consistent with structure. MS EI:M^(+•)168.1259 (M^(+•) 168.1263).

[1197] 2.6-{[1-(1H-Imidazol-1-ylmethyl)pentyl]oxy}-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone

[1198] Diethyl azodicarboxylate (0.16 mL, 0.99 mmol) was added over 10min to a mixture of6-Hydroxy-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone(300 mg, 0.99 mmol), 1-(1H-imidazol-1-yl)-2-hexanol (166 mg, 1.08 mmol),triphenylphosphine (259 mg, 0.99 mmol) and tetrahydrofuran (2 mL) undernitrogen. The resulting mixture was stirred for 5 d, whereupon it wasconcentrated and the residue was purified by dry-flash columnchromatography (SiO₂, 1-9% 2-propanol-dichloromethane) to give6-{[1-(1H-imidazol-1-ylmethyl)pentyl]oxy}-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenoneas a colorless foam, 283 mg, 62% yield. NMR spectrum was consistent withstructure. MS EI: M^(+•)466.1919 (M^(+•) 466.1926).

EXAMPLE 63n

[1199] Synthesis of6-[1-(1H-Imidazol-1-ylmethyl)propoxy]-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone(Compound 63n)

[1200] 1. 1-(1H-Imidazol-1-yl)-2-butanol

[1201] A solution of 1,2-epoxybutane (2.0 mL, 23 mmol) and imidazole(2.37 g, 35 mmol) in acetonitrile (20 mL) was stirred at reflux for 24h. The mixture was concentrated, taken up in water (30 mL) and extractedwith ethyl acetate (9×10 mL). The combined extracts were dried (Na₂SO₄)and concentrated. The residue was purified by flash columnchromatography (SiO₂, CH₂Cl₂-methanol-ammonium hydroxide 80:20:1) togive 1-(1H-imidazol-1-yl)-2-butanol (1.57 g, 48%) as a colorless oil.NMR spectrum was consistent with structure. MS EI: M^(+•) 140.0948(M^(+•) 140.0950).

[1202] 2.6-[1-(1H-Imidazol-1-ylmethyl)propoxy]-5-[(phenylsulfonyl)methyl]-3,4-dihydro-[(2H)-naphthalenone

[1203] Diethyl azodicarboxylate (0.16 mL, 0.99 mmol) was added over 10min to a mixture of6-hydroxy-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone(300 mg, 0.99 mmol), 1-(1H-imidazol-1-yl)-2-butanol (165 mg, 1.08 mmol),triphenylphosphine (260 mg, 0.99 mmol) and tetrahydrofuran (2 mL) undernitrogen. The resulting mixture was stirred for 6 d, whereupon it wasconcentrated. The residue was purified by dry-flash columnchromatography (SiO₂, 1-9% 2-propanol-dichloromethane) to give6-[1-(1H-imidazol-1-ylmethyl)propoxy]-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenoneas a foam, 125 mg, 29% yield. NMR spectrum was consistent withstructure. MS EI: M^(+•) 438.1608 (M+438.1613).

EXAMPLE 63o

[1204]

[1205] Synthesis of(±)-6-[2-(2-Methyl-imidazol-yl)-1-phenyl-ethoxy]-5-phenethyl-3,4-dihydro-2H-naphthalen-1-one(Compound 63o)

[1206] The title compound was prepared using the procedure of Example20, step 4 using6-hydroxy-5-(2-phenyl-ethyl)-3,4-dihydro-2H-naphthalen-1-one and2-methylimidazole.

[1207] The product was obtained as a white foam (0.34 g, 52% yield). MSAPCI 451 [M+H]⁺.

EXAMPLE 63p

[1208]

[1209] Synthesis of6-(2-Imidazol-yl-1-thiophen-2-yl-ethoxy)-5-(pyridine-2-sulfonylmethyl)-3,4-dihydro-2H-naphthalen-14-one(Compound 63p)

[1210] 1. 2-Imidazol-1-yl-N-methoxy-N-methyl-acetamide

[1211] 60% sodium hydride in oil (0.296 g, 7.4 mol) was washed withtetrahydrofuran and suspended in additional tetrahydrofuran (10 ml). Tothis was added imidazole (0.506 g, 7.43 mol) followed by stirring at 25°C. for 1 hour. To the mixture was added a solution of2-chloro-N-methoxy-N-methyl-acetamide (1.02 g, 7.4 mmol, prepared perTetrahedron Letters Vol. 30, No. 29, pp3779-80, 1989.) followed bystirring at 25° C. for 15. The mixture was filtered, and the filtratewas evaporated to an oil in vacuo and purifide by chromatography onsilica gel eluted with a gradient of chloroform to 10%methanol:chloroform giving a solid 0.46 g, 37% yield.

[1212] 2. 2-Imidazol-1-yl-1-thiophen-2-yl-ethanone

[1213] To magnesium turnings (0.16 g, 24 mmol) was added2-bromothiophene. To the mixture was added tetrahydrofuran (4 ml), acatalytic amount of iodine and additional tetrahydrofuran (6 ml). Themixture was heated to 50° C. giving solution of the magnesium metal. Thesolution was cooled and added to a mixture of2-Imidazol-1-yl-N-methoxy-N-methyl-acetamide in tetrahydrofuran (5 ml)at 0° C. This mixture was stirred for 16 hours and was poured into 20%ammonium chloride solution (20 ml), partitioned and extracted withtetrahydrofuran. The organic phase was diluted with ethyl ether andwashed with brine, dried over anhydrous magnesium sulfate andconcentrated in vacuo to a brown solid, 0.57 g, 58% yield. MS: APCI:M+1: 192.9 (M: 192.24).

[1214] 3. 2-Imidazol-1-yl-1-thiophen-2-yl-ethanol

[1215] 2-Imidazol-1-yl-1-thiophen-2-yl-ethanone (0.53 g, 2.76 mol) wasadded to a solution of sodium borohydride (0.11 g, 2.9 mol) in methanol(30 ml) at 0° C. The temperature was allowed to reach 25° C. for 1 hourfollowed by dilution with ethyl ether. The ethyl ether was washed with aminimal amount of saturated sodium bicarbonate solution, washed withbrine, dried over anhydrous magnesium sulfate and filtered. The filtratewas evaporated to a solid, 0.41 g, 77% yield, MS: APCI: M+1: 194.9 (M:194.26).

[1216] 4.6-(2-Imidazol-1-yl-1-thiophen-2-yl-ethoxy)-5-(pyridine-2-sulfonylmethyl)-3,4-dihydro-2H-naphthalen-1-one

[1217] In a manner similar to that of Example 10,6-Hydroxy-5-(pyridine-2-sulfonylmethyl-3,4-dihydro-2H-naphthalen-1-one(0.53 g, 1.7 mmol), and 2-Imidazol-1-yl-1-thiophen-2-yl-ethanol (0.37 g,1.9 mmol) gave a solid, 0.06 g, 7.3% yield. MS: APCI: M+1, 494.0 (M:493.6). Calcd. For C25H23N3O4S2, 0.1H2O, 0.06 CHCl3: Theory: C, 59.89;H, 4.66; N, 8.36; Cl, 1.27, H₂O 0.36 Found: C, 59.55; H, 4.65; N, 8.50;Cl, 1.29, H₂O 0.76

EXAMPLE 63q

[1218]

[1219] Synthesis of6-(2-Imidazol-1-yl-1-thiazol-2-yl-ethoxy)-5-(pyridine-2-sulfonylmethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 63q

[1220] 1. 2-Imidazol-1-yl-1-thiazol-2-yl-ethanone

[1221] To tetrahydrofuran (20 ml) was added tetramethylethylenediamine(1.16 g, 10 mmol) followed by 4 ml of a solution of n-butyllithium inhexanes, 2.5M. The mixture was cooled to −75° C. and 2-bromothiazole(1.64 g, 10 mmol) was added over 5 minutes. After stirring for 2 hoursat −75° C. a solution of 2-Imidazol-1-yl-N-methoxy-N-methyl-acetamide(1.4 g, 8.26 mmol) in tetrahydrofuran (20 ml) was added over 15 minutes.After stirring at −78° C. for 2 hours, the temperature was increased to−101° C. This mixture was poured into 1N citric acid solution, agitatedand extracted with ethyl ether. The pH of the aqueous phase was adjustedto 14 with 50% NaOH and extracted with dichloromethane. Thedichloromethane was dried over anhydrous magnesium sulfate andconcentrated in vacuo to a brown oil containing a solid. The oil wasdecanted and the solid was purified on a short plug of silica gel elutedwith dichloromethane, giving a solid, 0.92 g. Further chromatography ona Biotage 12s column eluted with a gradient of hexane to 20% chloroformgate the product as a solid, 0.528 g, 33% yield. MS: APCI: M+1: 193.3(M: 193.3).

[1222] 2. 2-Imidazol-1-yl-1-thiazol-2-yl-ethanol

[1223] 2-Imidazol-1-yl-1-thiazol-2-yl-ethanone (0.50 g, 2.6 mol) wasadded to a solution of sodium borohydride (0.099 g, 2.63 mol) inmethanol (30 ml) at 0° C. The temperature was allowed to reach 25° C.for 1 hour followed by evaporation in vacuo. To the residue was addedsodium bicarbonate solution and ethyl acetate, followed by agitation andseparation of the organic phase The aqueous phase was exhaustivelywashed with dichloromethane and the organic extracts were combined,dried over anhydrous magnesium sulfate and filtered. The filtrate wasevaporated to a solid and purified by chromatography on silica geleluted with chloroform. 0.23 g, 45% yield.

[1224] 3.6-(2-Imidazol-1-yl-1-thiazol-2-yl-ethoxy)-5-(pyridine-2-sulfonylmethyl)-3,4-dihydro-2H-naphthalen-1-one

[1225] In a manner similar to that of Example 10,6-Hydroxy-5-(pyridine-2-sulfonylmethyl-3,4-dihydro-2H-naphthalen-1-one(0.326 g, 1.03 mmol), and 2-Imidazol-1-yl-1-thiazol-2-yl-ethanol (0.230g, 1.18 mmol) gave a solid, 0.138 g, 27% yield. MS: APCI: M+1, 495.0 (M:494.6). Calcd. For C24H22N4O4S2, 0.3H2O, 0.05 CHCl3:

[1226] Theory: C, 57.09; H, 4.39; N, 11.07; Cl, 1.05H₂O 1.07 Found: C,56.69; H, 4.81; N, 11.19; Cl, 1.11, H₂O 1.46.

EXAMPLE 63r

[1227]

[1228] Synthesis of6-[2-(2-Amino-imidazol-1-yl)-1-phenyl-ethoxy]-5-phenethyl-3,4-dihydro-2H-naphthalen-1-one(Compound 63r)

[1229] 1. 2-(2-Nitro-imidazol-1-yl)-1-pyridin-3-yl-ethanone

[1230] Sodium metal (0.41 g, 0.0177 mol) was dissolved in methanol (8ml) and added to a solution of 2-nitroimidazole (2 g, 0.0177 mol) in 20ml dimethylformamide. The mixture was stirred for 30 minutes, followedby addition of phenacyl bromide (3.58 g, 18 mmol) The mixture was heatedto 130° C. for 1 hour, giving a solid precipitate. The solvents wereremoved in vacuo and the residue was taken up into ethyl acetate. Thesolution was washed with water and brine, dried over anhydrous magnesiumsulfate, filtered and evaporated to give a solid precipitate. The pastewas diluted with ethyl ether, filtered, washed with ether and dried invacuo giving a yellow solid 2.7 g, 66% yield, mp125-127° C. MS: APCI:M+1: 232.0 (M: 231.4).

[1231] 2. 2-(2-Nitro-imidazol-1-yl)-1-pyridin-3-yl-ethanol

[1232] To methanol at −35° C. was added sodium borohydride (0.43 g, 11.3mmol) followed by 2-(2-Nitro-imidazol-1-yl)-1-pyridin-3-yl-ethanone(2.63 g, 11.3 mmol) suspended in methanol (25 ml). The mixture waswarmed gradually to 25° C. over 1 hour, followed by evaporation in vacuoto a solid. The solid was resuspended in ethyl aceatate, washed withwater, brine, dried over anhydrous magnesium sulfate and filtered. Thefiltrate was concentrated in vacuo and ethyl ether was added, giving asolid precipitate. The solid was dried in vacuo, 2.0 g, 76% yield.

[1233] 3.6-[2-(2-Nitro-imidazol-1-yl)-1-phenyl-ethoxy]-5-phenethyl-3,4-dihydro-2H-naphthalen-1-one

[1234] In a manner similar to that of Example 20 Step4,6-Hydroxy-5-phenethyl-3,4-dihydro-2H-naphthalen-1-one (0.86 g, 3.23mmol), and): 2-(2-Nitro-imidazol-1-yl)-1-pyridin-3-yl-ethanol gave asolid, 0.92 g, 51% yield, mp 185-188° C. MS: APCI: M+1, 482.2 (M:481.6). Calcd. For C29H27N3O4, 0.03H2O: Theory: C, 71.87; H, 5.62; N,8.66; Cl, 0.66 Found: C, 71.87; H, 5.79; N, 8.62; Cl, 0.64.

[1235] 4.6-[2-(2-Amino-imidazol-1-yl)-1-phenyl-ethoxy]-5-phenethyl-3,4-dihydro-2H-naphthalen-1-one

[1236] To a mixture of methanol (25 ml) and acetic acid (2 ml) was added6-[2-(2-Nitro-imidazol-1-yl)-1-phenyl-ethoxy]-5-phenethyl-3,4-dihydro-2H-naphthalen-1-one(0.57 g, 1.18 mmol) followed by heating to 80° C. to give solution. Tothe mixture was added iron powder, (0.66 g, 11.9 mmol, Aldrich 99.99%,10 micron) followed by heating at reflux for 3 hours. The mixture wasevaporated in vacuo to a gummy solid. The residue was suspended in ethylacetate, filtered, and washed with saturated sodium bicarbonate. Theorganic phase was washed with brine, dried over anhydrous magnesiumsulfate, filtered and evaporated to a solid. The solid was purified bychromatography on a Biotage 12s silica gel column eluted with a gradientof chloroform to 10% methanol:chloroform. The product was recovered as ayellow foam, 0.148 g, 28% yield, MS: APCI: M+1, 452.3 (M: 451.6).

[1237] Calcd. For C29H29N3O2, 0.15H2O, 0.05CHCl3:

[1238] Theory: C, 75.81; H, 6.43; N, 9.13; Cl, 1.16, H₂O 0.58. Found: C,75.71; H, 6.46; N, 8.91; Cl, 1.24, H2O 0.59.

EXAMPLE 64

[1239] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(methoxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 64)

[1240] 1. 6-Hydroxy-5-(methoxymethyl)-2,3,4-trihydronaphthalen-1-one

[1241] To a heated solution (64° C.) of5-chloromethyl-6-hydroxy-2,3,4-trihydronaphthalen-1-one (8.1 g, 38.5mmol) in methanol (250 mL) under N₂ is slowly addeddiisopropylethylamine (8.05 mL, 46.2 mmol) in 2 mL methanol via anaddition funnel. The reaction is stirred at 64° C. for 1 hour, cooledand concentrated in vacuo to a pink syrup. The residue is dissolved inchloroform (100 mL) and washed with 1 M citric acid (2×30 mL) and thenbrine (1×30 mL), and dried over anhydrous sodium sulfate. The solutionis evaporated to dryness in vacuo and subsequently in a vacuum oven toyield 7.6 g of pink crystals. Low resolution mass spectrum (APCI) m/z207 [M+H]⁺ (H. Sugihara, K. Ukawa, H. Kuriki, M. Nishikawa, and Y.Sanno, Chem. Pharm. Bull. (Tokyo) 1977;25:2988).

[1242] 2.6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(methoxymethyl)-2,3,4-trihydronaphthalen-1-one

[1243] 6-Hydroxy-5-(methoxymethyl)-2,3,4-trihydronaphthalen-1-one (9.2g, 44.7 mmol), (R)-2-imidazol-1-yl-1-phenylethanol (8.4 g, 44.7 mmol)and polystyrene triphenylphosphine resin (40.5 g, loading 1.65 mmol/g,Argonaut Technologies) are combined in a 75×300 mm peptide reactionvessel with dichloromethane (800 mL). To this heterogeneous mixture iscarefully added diethylazodicarboxylate (10.5 mL, 67 mmol) in 3 portionsvia syringe. After mixing by inversion at RT (12 hours), the spenttriphenyphosphine resin is removed by gravity filtration and washed withtetrahydrofuran (1×400 mL) and dichloromethane (2×400 mL). The combinedfiltrate and washes are concentrated in vacuo to yield a yellow-brownoil which is dissolved in methanol (200 mL) and treated with macroporoussulfonic acid resin (60 g, loading 1.45 mmol/g, Argonaut TechnologiesInc.). After mixing by inversion (1 hour), the sulfonic acid resin iscollected by gravity filtration and washed with methanol (4×50 mL),tetrahydrofuran (2×50 mL), and methanol (2×50 mL). Elution of productfrom the resin with 2.0 M ammonia in methanol (150 mL) and concentrationin vacuo yields a yellow oil that is purified by flash silica gelchromatography (ethyl acetate/hexanes/triethylamine 18:1:1) to give 15.4g of the desired product (Compound 64) as a colorless glass. Lowresolution mass spectrum (APCI) m/z 377 [M+H]⁺.

EXAMPLE 65

[1244] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-methoxphenoxy)methyl)]-2,3,4-trihydronaphthalen-1-one(Compound 65)

[1245] 1.6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(bromomethyl)-2,3,4-trihydronaphthalen-1-oneHydrobromide

[1246] An argon flushed 1 L round bottomed flask equipped with a refluxcondenser and a gas inlet adapter is charged with6-((1S)-2-imidazolyl-1-phenylethoxy)-5-(methoxymethyl)-2,3,4-trihydronaphthalen-1-one(14.3 g, 38.1 mmol) and glacial acetic acid (300 mL). The reaction flaskis placed in a 50° C. oil bath and 30% hydrogen bromide in acetic acid(20.6 mL, 76.3 mmol) is carefully introduced via syringe. The resultingmixture is allowed to stir at 50° C. (4 hours), then cooled to RT andconcentrated in vacuo to give an orange foam. Re-crystallization (2×)from chloroform diethyl ether yields 21.3 g of off-white fluffycrystals. Low resolution mass spectrum (APCI) m/z 426 [M+H]⁺.

[1247] 2.6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-methoxyphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one

[1248] Sodium hydride 60% in oil (19.2 mg, 0.48 mmol, Aldrich), freshlydistilled tetrahydrofuran (2 mL), and 4-methoxyphenol in 1 mL THF (60mg, 0.48 mmol, Aldrich) are introduced into an argon purged 15 mL roundbottom flask. The reaction mixture is stirred until the slurry ishomogeneous. The product from step 1 (100 mg, 0.19 mmol) in THF (4.0 mL)is added via syringe to a stirring phenoxide solution. The mixture isheated to reflux with a heat gun (1 minute), cooled, and concentrated invacuo to yield a pinkish residue. The resulting residue is dissolved inethyl acetate (4.0 mL) and washed with a 2 M NaOH solution (4×2.0 mL).The organic layer is concentrated to an oil, diluted with methanol (8.0mL), and stirred with macroporous polystyrene sulfonic acid resin (330mg, loading 1.45 mmol/g, Argonaut Technologies, Inc.) for 1 hour. Theresin is collected by gravity filtration and washed with methanol andthen THF (3.0 mL each). Elution of the product from the resin with 2.0 Mammonia in methanol (3.0 mL) and concentration in vacuo yields 52 mg ofproduct (Compound 65) as a glass. Low resolution mass spectrum (APCI)m/z 469 [M+H]⁺.

EXAMPLE 66

[1249] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(phenoxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 66)

[1250] Phenol (94 mg, 1.0 mmol, 1.0 M in THF) and excess sodium hydride(60% in oil) (30 mg) are combined in a septum capped, argon purged2-dram vial. After bubbling ceases (15.0 minutes), the heterogeneoussolution was removed by syringe, and filtered by negative pressurethrough a 0.45 μM disk syringe filter (Whatman PTFE) into an evacuated2-dram vial containing the product from Example 65, step 1 (100 mg, 0.19mmol, 0.19 M in THF/acetonitrile (1:1)). The vial is capped with aTeflon lined cap and placed in a heater-shaker at 60° C. for 45 minutes.The reaction mixture is cooled to room temperature, concentrated invacuo, diluted with chloroform (4.0 mL), and washed with 2.0 M NaOH(2×4.0 mL). The organic layer is dried over anhydrous sodium sulfate,concentrated under a stream of N₂ gas, diluted in methanol (4.0 mL), andtreated with macroporous sulfonic acid resin (300 mg, Loading 1.45mmol/g, Argonaut Technologies, Inc.) for 1 hour by gentle magneticstirring. The resin is collected using gravity filtration, washedserially with methanol, ethyl acetate, and methanol, respectively (3.0mL each). Elution of the product from the resin with 2.0 M ammonia inmethanol and evaporation of the solvent via a N₂ gas stream produces 58mg of desired product (Compound 66) as a glass. Low resolution massspectrum (APCI) m/z 439 [M+H]⁺.

EXAMPLE 67

[1251] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[[3-(tert-butyl)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one(Compound 67)

[1252] According to the method in Example 66, 3-tert-butylphenol (150mg, 1.0 mmol, 1.0 M in THF) is combined with the product from Example65, step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) toproduce 62 mg of the desired product (Compound 67) as a glass. Lowresolution mass spectrum (APCI) m/z 495 [M+H]⁺.

EXAMPLE 68

[1253] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[2-(methylethyl)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one (Compound 68)

[1254] According to the method in Example 66, 2-isopropylphenol (136 mg,1.0 mmol, 1.0 M in THF) is combined with product from Example 65, step 1(100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) to produce 60 mgof the desired product (Compound 68) as a glass. Low resolution massspectrum (APCI) m/z 481 [M+H]⁺.

EXAMPLE 69

[1255] Synthesis of6-((1S)-2-imidazolyl-1-phenylethoxy)-5-[(3-chlorophenoxy)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 69)

[1256] According to the method in Example 66, 3-chlorophenol (129 mg,1.0 mmol, 1.0 M in THF) is combined with the product from Example 65,step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) to produce45 mg of the desired product (Compound 69) as a glass. Low resolutionmass spectrum (APCI) m/z 473 [M+H]⁺.

EXAMPLE 70

[1257] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[2-methyl-5-(methylethyl)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one (Compound 70)

[1258] According to the method in Example 66, 5-isoproyl-2-methyl-phenol(150 mg, 1.0 mmol, 1.0 M in THF) is combined with the product fromExample 65, step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1))to produce 59 mg of the desired product (Compound 70) as a glass. Lowresolution mass spectrum (APCI) m/z 495 [M+H]⁺.

EXAMPLE 71

[1259] Synthesis of6-((1S)-2-imidazolyl-1-phenylethoxy)-5-[(3,5-dimethoxyphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 71)

[1260] According to the method in Example 66, 3,5-dimethoxy-phenol (154mg, 1.0 mmol, 1.0 M in THF) is combined with the product from Example65, step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) toproduce 68 mg of the desired product (Compound 71) as a glass. Lowresolution mass spectrum (APCI) m/z 499 [M+H]⁺.

EXAMPLE 72

[1261] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[4-(methylethyl)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one(Compound 72)

[1262] According to the method in Example 66, 4-isopropyl-phenol (136mg, 1.0 mmol, 1.0 M in THF) is combined with the product from Example65, step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) toproduce 63 mg of the desired product (Compound 72) as a glass. Lowresolution mass spectrum (APCI) m/z 481 [M+H]⁺.

EXAMPLE 73

[1263] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-5,6,7,8-tetrahydro-naphthyloxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 73)

[1264] According to the method in Example 66,5,6,7,8-tetrahydro-naphthalen-2-ol (148 mg, 1.0 mmol, 1.0 M in THF) iscombined with the product from Example 65, step 1 (100 mg, 0.19 mmol,0.19 M in THF/acetonitrile (1:1)) to produce 69 mg of the desiredproduct (Compound 73) as a glass. Low resolution mass spectrum (APCI)m/z 493 [M+H]⁺.

EXAMPLE 74

[1265] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[3-(methylethyl)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one (Compound 74)

[1266] According to the method in Example 66, 3-isopropyl-phenol (136mg, 1.0 mmol, 1.0 M in THF) is combined with the product from Example65, step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) toproduce 65 mg of the desired product (Compound 74) as a glass. Lowresolution mass spectrum (APCI) m/z 481 [M+H]⁺.

EXAMPLE 75

[1267] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-pyrrolylphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 75)

[1268] According to the method in Example 66, 4-pyrrol-1-yl-phenol (159mg, 1.0 mmol, 1.0 M in THF) is combined with the product from Example65, step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) toproduce 64 mg of the desired product (Compound 75) as a glass. Lowresolution mass spectrum (APCI) m/z 504 [M+H]⁺.

EXAMPLE 76

[1269] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(indol-4-yloxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 76)

[1270] According to the method in Example 66, 1H-indol-4-ol (133 mg, 1.0mmol, 1.0 M in THF) is combined with the product from Example 65, step 1(100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) to produce 67 mgof the desired product (Compound 76) as a glass. Low resolution massspectrum (APCI) m/z 478 [M+H]⁺.

EXAMPLE 77

[1271] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[2-(methylethoxy)phenyl]methyl}-2,3,4-trihydronaphthalen-4-1-one (Compound 77)

[1272] According to the method in Example 66, 2-isopropoxy-phenol (152mg, 1.0 mmol, 1.0 M in THF) is combined with the product from Example65, step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) toproduce 64 mg of the desired product (Compound 77) as a glass. Lowresolution mass spectrum (APCI) m/z 497 [M+H]⁺.

EXAMPLE 78

[1273] Synthesis of6-((1S)-2-Imidazolyl-4-phenylethoxy)-5-[(2-ethoxyphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 78)

[1274] According to the method in Example 66, 2-ethoxyphenol (138 mg,1.0 mmol, 1.0 M in THF) is combined with the product from Example 65,step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) to produce55 mg of the desired product (Compound 78) as a glass. Low resolutionmass spectrum (APCI) m/z 483 [M+H]⁺.

EXAMPLE 79

[1275] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-ethoxyphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 79)

[1276] According to the method in Example 66, 4-ethoxyphenol (138 mg,1.0 mmol, 1.0 M in THF) is combined with the product from Example 65,step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) to produce64 mg of the desired product (Compound 79) as a glass. Low resolutionmass spectrum (APCI) m/z 483 [M+H]⁺.

EXAMPLE 80

[1277] Synthesis of6-(1S)-2-Imidazolyl-1-phenylethoxy)-5-[(3-ethylphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 80)

[1278] According to the method in Example 66, 3-ethylphenol (122 mg, 1.0mmol, 1.0 M in THF) is combined with the product from Example 65, step 1(100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) to produce 64 mgof the desired product (Compound 80) as a glass. Low resolution massspectrum (APCI) m/z 467 [M+H]⁺.

EXAMPLE 81

[1279] Synthesis of Methyl2-{[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]methoxy}benzoate(Compound 81)

[1280] According to the method in Example 66, methyl 2-hydroxybenzoate(152 mg, 1.0 mmol, 1.0 M in THF) is combined with the product fromExample 65, step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1))to produce 14 mg of the desired product (Compound 81) as a glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 497 [M+H]⁺.

EXAMPLE 82

[1281] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(6-methyl(3-pyridyloxy))methyl]-2,3,4-trihydronaphthalen-1-one(Compound 82)

[1282] According to the method in Example 66, 6-methyl-pyridin-3-ol (109mg, 1.0 mmol, 1.0 M in THF) is combined with the product from Example65, step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) toproduce 27 mg of the desired product (Compound 82) as a glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 454 [M+H]⁺.

EXAMPLE 83

[1283] Synthesis of6-((1S)-2-imidazolyl-1-phenylethoxy)-5-[(6-methyl(3-pyridyloxy))methyl]-2,3,4-trihydronaphthalen-1-one (Compound 83)

[1284] According to the method in Example 66, 5-chloropyridin-3-ol (129mg, 1.0 mmol, 1.0 M in THF) is combined with the product from Example65, step 1 (100 mg, 0. 19 mmol, 0.19 M in THF/acetonitrile (1:1)) toproduce 38 mg of the desired product (Compound 83) as a glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 474 [M+H]⁺.

EXAMPLE 84

[1285] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-ethylphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 84)

[1286] According to the method in Example 66, 4-ethylphenol (122 mg, 1.0mmol, 1.0 M in THF) is combined with the product from Example 65, step 1(100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) to produce 26 mgof the desired product (Compound 84) as a glass. Low resolution massspectrum (LC-MS, APCI) m/z 467 [M+H]⁺.

EXAMPLE 85

[1287] Synthesis of6-(1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-naphthyloxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 85)

[1288] According to the method in Example 66, naphthalen-2-ol (144 mg,1.0 mmol, 1.0 M in THF) is combined with the product from Example 65,step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) to produce30 mg of the desired product (Compound 85) as a glass. Low resolutionmass spectrum (LC-MS, APCI) m/z 489 [M+H]⁺.

EXAMPLE 86

[1289] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-chloro-5-methylphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 86)

[1290] According to the method in Example 66, 2-chloro-5-methylphenol(142 mg, 1.0 mmol, 1.0 M in THF) is combined with the product fromExample 65, step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1))to produce 27 mg of the desired product (Compound 86) as a glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 487 [M+H]⁺.

EXAMPLE 87

[1291] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[2-(methylpropyl)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one (Compound 87)

[1292] According to the method in Example 66, 2-sec-butylphenol (150 mg,1.0 mmol, 1.0 M in THF) is combined with the product from Example 65,step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) to produce20 mg of the desired product (Compound 87) as a glass. Low resolutionmass spectrum (LC-MS, APCI) m/z 495 [M+H]⁺.

EXAMPLE 88

[1293] Synthesis of Methyl3-{[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]methoxy}benzoate(Compound 88)

[1294] According to the method in Example 66, methyl 3-hydroxybenzoate(152 mg, 1.0 mmol, 1.0 M in THF) is combined with the product fromExample 65, step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1))to produce 14 mg of the desired product (Compound 88) as a glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 497 [M+H]⁺.

EXAMPLE 89

[1295] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2,4,6-trimethylphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 89)

[1296] According to the method in Example 66, 2,4,6-trimethylphenol (136mg, 1.0 mmol, 1.0 M in THF) is combined with the product from Example65, step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) toproduce 35 mg of the desired product (Compound 89) as a glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 481 [M+H]⁺.

EXAMPLE 90

[1297] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[4-(methylpropyl)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one (Compound 90)

[1298] According to the method in Example 66, 4-sec-butylphenol (150 mg,1.0 mmol, 1.0 M in THF) is combined with the product from Example 65,step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) to produce16 mg of the desired product (Compound 90) as a glass. Low resolutionmass spectrum (LC-MS, APCI) m/z 495 [M+H]⁺.

EXAMPLE 91

[1299] Synthesis of6-((1S)-2-imidazolyl-1-phenylethoxy)-5-{[4-(trifluoroethyl)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one (Compound 91)

[1300] According to the method in Example 66, 4-trifluoromethylphenol(162 mg, 1.0 mmol, 1.0 M in THF) is combined with the product fromExample 65, step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1))to produce 27 mg of the desired product (Compound 91) as a glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 507 [M+H]⁺.

EXAMPLE 92

[1301] Synthesis of6-((1S)-2-imidazolyl-1-phenylethoxy)-5-(2H-benzo[d]1,3-dioxolan-5-yloxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 92)

[1302] According to the method in Example 66, benzo[1,3]dioxol-5-ol (138mg, 1.0 mmol, 1.0 M in THF) is combined with the product from Example65, step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) toproduce 23 mg of the desired product (Compound 92) as a glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 483 [M+H]⁺.

EXAMPLE 93

[1303] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2H-benzo[d]1,3-dioxolan-5-yloxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 93)

[1304] According to the method in Example 66, 4-chloro-3-methyl-phenol(142 mg, 1.0 mmol, 1.0 M in THF) is combined with the product fromExample 65, step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1))to produce 32 mg of the desired product (Compound 93) as a glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 487 [M+H]⁺.

EXAMPLE 94

[1305] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy))-5-(8-quinolyloxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 94)

[1306] According to the method in Example 66, quinolin-8-ol (145 mg, 1.0mmol, 1.0 M in THF) is combined with the product from Example 65, step 1(100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) to produce 40 mgof the desired product (Compound 94) as a glass. Low resolution massspectrum (LC-MS, APCI) m/z 490 [M+H]⁺.

EXAMPLE 95

[1307] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(8-quinolyloxymethyl)-2,3,4-trihydronaphthalen-41-one(Compound 95)

[1308] According to the method in Example 66, 3-dimethylaminophenol (137mg, 1.0 mmol, 1.0 M in THF) is combined with the product from Example65, step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) toproduce 32 mg of the desired product (Compound 95) as a glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 482 [M+H]⁺.

EXAMPLE 96

[1309] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[4-(trifluoromethoxy)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one (Compound 96)

[1310] According to the method in Example 66, 4-trifluoromethoxy-phenol(178 mg, 1.0 mmol, 1.0 M in THF) is combined with the product fromExample 65, step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1))to produce 29 mg of the desired product (Compound 96) as a glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 523 [M+H]⁺.

EXAMPLE 97

[1311] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[4-(phenoxy)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one(Compound 97)

[1312] According to the method in Example 66, 4-phenoxyphenol (186 mg,1.0 mmol, 1.0 M in THF) is combined with the product from Example 65,step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) to produce32 mg of the desired product (Compound 97) as a glass. Low resolutionmass spectrum (LC-MS, APCI) m/z 531 [M+H]⁺.

EXAMPLE 98

[1313] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-chlorophenoxy)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 98)

[1314] According to the method in Example 66, 4-chlorophenol (128 mg,1.0 mmol, 1.0 M in THF) is combined with the product from Example 65,step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) to produce34 mg of the desired product (Compound 98) as a glass. Low resolutionmass spectrum (LC-MS, APCI) m/z 473 [M+H]⁺.

EXAMPLE 99

[1315] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(3-methylphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 99)

[1316] According to the method in Example 66, 3-methylphenol (108 mg,1.0 mmol, 1.0 M in THF) is combined with the product from Example 65,step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) to produce36 mg of the desired product (Compound 99) as a glass. Low resolutionmass spectrum (LC-MS, APCI) m/z 453 [M+H]⁺.

EXAMPLE 100

[1317] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-methylphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 100)

[1318] According to the method in Example 66, 4-methylphenol (108 mg,1.0 mmol, 1.0 M in THF) is combined with the product from Example 65,step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) to produce37 mg of the desired product (Compound 100) as a glass. Low resolutionmass spectrum (LC-MS, APCI) m/z 453 [M+H]⁺.

EXAMPLE 101

[1319] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-fluorophenoxy)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 101)

[1320] According to the method in Example 66, 2-fluorophenol (112 mg,1.0 mmol, 1.0 M in THF) is combined with the product from Example 65,step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) to produce38 mg of the desired product (Compound 101) as a glass. Low resolutionmass spectrum (LC-MS, APCI) m/z 457 [M+H]⁺.

EXAMPLE 102

[1321] Synthesis of6-(1S)-2-Imidazolyl-1-phenylethoxy)-5-[(3-fluorophenoxy)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 102)

[1322] According to the method in Example 66, 3-fluorophenol (112 mg,1.0 mmol, 1.0 M in THF) is combined with the product from Example 65,step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) to produce33 mg of the desired product (Compound 102) as a glass. Low resolutionmass spectrum (LC-MS, APCI) m/z 457 [M+H]⁺.

EXAMPLE 103

[1323] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-fluorophenoxy)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 103)

[1324] According to the method in Example 66, 4-fluorophenol (112 mg,1.0 mmol, 1.0 M in THF) is combined with the product from Example 65,step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) to produce5 mg of the desired product (Compound 103) as a glass. Low resolutionmass spectrum (LC-MS, APCI) m/z 457 [M+H]⁺.

EXAMPLE 104

[1325] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(naphenyloxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 104)

[1326] According to the method in Example 66, naphthalen-1-ol (144 mg,1.0 mmol, 1.0 M in THF) is combined with the product from Example 65,step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) to produce41 mg of the desired product (Compound 104) as a glass. Low resolutionmass spectrum (LC-MS, APCI) m/z 489 [M+H]⁺.

EXAMPLE 105

[1327] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(3-methoxyphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 105)

[1328] According to the method in Example 66, 3-methoxyphenol (124 mg,1.0 mmol, 1.0 M in THF) is combined with the product from Example 65,step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) to produce32 mg of the desired product (Compound 105) as a glass. Low resolutionmass spectrum (LC-MS, APCI) m/z 469 [M+H]⁺.

EXAMPLE 106

[1329] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-chlorophenoxy)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 106)

[1330] According to the method in Example 66, 2-chlorophenol (128 mg,1.0 mmol, 1.0 M in THF) is combined with the product from Example 65,step 1 (100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) to produce32 mg of the desired product (Compound 106) as a glass. Low resolutionmass spectrum (LC-MS, APCI) m/z 473 [M+H]⁺.

EXAMPLE 107

[1331] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(6-quinolyloxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 107)

[1332] According to the method in Example 66, quinolin-5-ol (145 mg, 1.0mmol, 1.0 M in THF) is combined with the product from Example 65, step 1(100 mg, 0.19 mmol, 0.19 M in THF/acetonitrile (1:1)) to produce 48 mgof the desired product (Compound 107) as a glass. Low resolution massspectrum (LC-MS, APCI) m/z 490 [M+H]⁺.

EXAMPLE 108

[1333] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(6-quinolyloxymethyl)-2,3,4-trihydronaphthalen-1-one(Compound 108))

[1334] 3-Chlorobenzenethiol (144 mg, 1.0 mmol, 1.0 M in THF) and6-((1S)-2-imidazolyl-1-phenylethoxy)-5-(bromomethyl)-2,3,4-trihydronaphthalen-1-onehydrobromide (Example 65, step 1) (100 mg, 0.198 mmol, 0.10 M inTHF/acetonitrile (1:1)) are combined in a 2-dram Teflon capped vial andplaced in a heater-shaker at 60° C. (295 rpm, 1 hour). The reactionmixture is cooled to RT, diluted with ethyl acetate (3 mL), and washedwith 2 M NaOH (2×2.0 mL) and then brine (1×2.0 mL). The organic layer isconcentrated to approximately 1.0 mL total volume, diluted with methanol(3.0 mL), treated with macroporous polystyrene sulfonic acid resin (200mg, loading 1.45 mmol/g, Argonaut Technologies, Inc.). The resultingheterogeneous mixture is placed on a short stroke shaker at 450 rpm for1 hour. The sulfonic acid resin is collected by gravity filtration andwashed sequentially with methanol, ethyl acetate, and methanol (4.0 mLeach). Elution of product from the sulfonic acid resin with 2.0 Mammonia in methanol and evaporation of the solvent provides 9 mg of thedesired sulfide (Compound 108) as a tan glass. Low resolution massspectrum (LC-MS, APCI) m/z 489 [M+H]⁺.

EXAMPLE 109

[1335] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-biomophenylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 109)

[1336] According to the method of Example 108, 4-bromobenzenethiol (189mg, 1.0 mmol, 1.0 M in THF) is combined with the product from Example65, step 1 (100 mg, 0.198 mmol, 0.10 M in THF/acetonitrile (1:1)) toafford 7 mg of the desired sulfide (Compound 109) as a tan glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 533 [M+H]⁺.

EXAMPLE 110

[1337] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-fluorophenylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 110)

[1338] According to the method of Example 108, 4-fluorobenzenethiol (128mg, 1.0 mmol, 1.0 M in THF) is combined with the product from Example65, step 1 (100 mg, 0.198 mmol, 0.10 M in THF/acetonitrile (1:1)) toafford 36 mg of the desired sulfide (Compound 110) as a tan glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 472 [M+H]⁺.

EXAMPLE 111

[1339] Synthesis ofN-(4-{[2-((1S)-2-Imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]methylthio}phenyl)acetamide(Compound 111)

[1340] According to the method of Example 108,N-(4-mercapto-phenyl)acetamide (167 mg, 1.0 mmol, 1.0 M in THF) iscombined with the product from Example 65, step 1 (100 mg, 0.198 mmol,0.10 M in THF/acetonitrile (1:1)) to afford 56 mg of the desired sulfide(Compound 111) as a tan glass. Low resolution mass spectrum (LC-MS,APCI) m/z 511 [M+H]⁺.

EXAMPLE 112

[1341] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-hydroxyphenylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 112)

[1342] According to the method of Example 108, 4-mercaptophenol (126 mg,1.0 mmol, 1.0 M in THF) is combined with the product from Example 65,step 1 (100 mg, 0.198 mmol, 0.10 M in THF/acetonitrile (1:1)) to afford23 mg of the desired sulfide (Compound 112) as a tan glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 470 [M+H]⁺.

EXAMPLE 113

[1343] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-methylphenylthio)methyl]-2,3,4-trihydronaphthalen-4-1-one (Compound 113)

[1344] According to the method of Example 108, 4-methylbenzenethiol (124mg, 1.0 mmol, 1.0 M in THF) is combined with the product from Example65, step 1 (100 mg, 0.198 mmol, 0.10 M in THF/acetonitrile (1:1)) toafford 34 mg of the desired sulfide (Compound 113) as a tan glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 468 [M+H]⁺.

EXAMPLE 114

[1345] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-methylpropylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 114)

[1346] According to the method of Example 108, 2-methylpropane-1]-thiol(90 mg, 1.0 mmol, 1.0 M in THF) is combined with the product fromExample 65, step 1 (100 mg, 0.198 mmol, 0.10 M in THF/acetonitrile(1:1)) to afford 36 mg of the desired sulfide (Compound 114) as a tanglass. Low resolution mass spectrum (LC-MS, APCI) m/z 434 [M+H]⁺.

EXAMPLE 115

[1347] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-hydroxyethylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 115)

[1348] According to the method of Example 108, 2-mercaptoethanol (78 mg,1.0 mmol, 1.0 M in THF) is combined with the product from Example 65,step 1 (100 mg, 0.198 mmol, 0.10 M in TH-F/acetonitrile (1:1)) to afford40 mg of the desired sulfide (Compound 115) as a tan glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 422 [M+H]⁺.

EXAMPLE 116

[1349] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-phenylethylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 116)

[1350] According to the method of Example 108, 2-phenyl-ethanethiol(1138 mg, 1.0 mmol, 1.0 M in TIE) is combined with the product fromExample 65, step 1 (100 mg, 0.198 mmol, 0.10 M in THF/acetonitrile(1:1)) to afford 40 mg of the desired sulfide (Compound 116) as a tanglass. Low resolution mass spectrum (LC-MS, APCI) m/z 482 [M+H]⁺.

EXAMPLE 117

[1351] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(cyclohexylthiomethyl)-2,3,4-trihydronaphthalen-1-one(Compound 117)

[1352] According to the method of Example 108, cyclohexanethiol (1116mg, 1.0 mmol, 1.0 M in THF) is combined with the product from Example65, step 1 (100 mg, 0.198 mmol, 0.10 M in THF/acetonitrile (1:1)) toafford 39 mg of the desired sulfide (Compound 117) as a tan glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 460 [M+H]⁺.

EXAMPLE 118

[1353] Synthesis of Methyl3-{[2-((1S)-2-Imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]methylthio}propanoate(Compound 118)

[1354] According to the method of Example 108, 3-mercapto-propionic acidmethyl ester (120 mg, 1.0 mmol, 1.0 M in THF) is combined with theproduct from Example 65, step 1 (100 mg, 0.198 mmol, 0.10 M inTHF/acetonitrile (1:1)) to afford 39 mg of the desired sulfide (Compound118) as a tan glass. Low resolution mass spectrum (LC-MS, APCI) m/z 464[M+H]⁺.

EXAMPLE 119

[1355] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(imidazol-2-ylthiomethyl)-2,3,4-trihydronaphthalen-1-one(Compound 119)

[1356] According to the method of Example 108, 1H-imidazole-2-thiol (100mg, 1.0 mmol, 1.0 M in THF) is combined with the product from Example65, step 1 (100 mg, 0.198 mmol, 0.10 M in THF/acetonitrile (1:1)) toafford 46 mg of the desired sulfide (Compound 119) as a tan glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 444 [M+H]⁺.

EXAMPLE 120

[1357] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(1H-1,2,4-triazol-3-ylthiomethyl)-2,3,4-trihydronaphthalen-1-one(Compound 120)

[1358] According to the method of Example 108,1H-[1,2,4]triazole-3-thiol (101 mg, 1.0 mmol, 1.0 M in THF) is combinedwith the product from Example 65, step 1 (100 mg, 0.198 mmol, 0.10 M inTHF/acetonitrile (1:1)) to afford 20 mg of the desired sulfide (Compound120) as a tan glass. Low resolution mass spectrum (LC-MS, APCI) m/z 445[M+H]⁺.

EXAMPLE 121

[1359] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(1-methylimidazol-2-ylthio)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 121)

[1360] According to the method of Example 108,1-methyl-1H-imidazole-2-thiol (114 mg, 1.0 mmol, 1.0 M in THF) iscombined with the product from Example 65, step 1 (100 mg, 0.198 mmol,0.10 M in THF/acetonitrile (1:1)) to afford 51 mg of the desired sulfide(Compound 121) as a tan glass. Low resolution mass spectrum (LC-MS,APCI) m/z 458 [M+H]⁺.

EXAMPLE 122

[1361] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(benzothiazol-2-ylthiomethyl)-2,3,4-trihydronaphthalen-1-one(Compound 122)

[1362] According to the method of Example 108, 1H-benzoimidazole-2-thiol(150 mg, 1.0 mmol, 1.0 M in THF) is combined with the product fromExample 65, step 1 (100 mg, 0.198 mmol, 0.10 M in THF/acetonitrile(1:1)) to afford 45 mg of the desired sulfide (Compound 122) as a tanglass. Low resolution mass spectrum (LC-MS, APCI) m/z 494 [M+H]⁺.

EXAMPLE 123

[1363] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(5-chlorobenzothiazol-2-ylthio)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 123)

[1364] According to the method of Example 108,5-chlorobenzothiazole-2-thiol (201 mg, 1.0 mmol, 1.0 M in THF) iscombined with the product from Example 65, step 1 (100 mg, 0.198 mmol,0.10 M in THF/acetonitrile (1:1)) to afford 5 mg of the desired sulfide(Compound 123) as a tan glass. Low resolution mass spectrum (LC-MS,APCI) m/z 545 [M+H]⁺.

EXAMPLE 124

[1365] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-furylthiomethyl)-2,3,4-trihydronaphthalen-1-one(Compound 124)

[1366] According to the method of Example 108, furan-2-ylmethanethiol(114 mg, 1.0 mmol, 1.0 M in THF) is combined with the product fromExample 65, step 1 (100 mg, 0.198 mmol, 0.10 M in THF/acetonitrile(1:1)) to afford 39 mg of the desired sulfide (Compound 124) as a tanglass. Low resolution mass spectrum (LC-MS, APCI) m/z 458 [M+H]⁺.

EXAMPLE 125

[1367] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(5-nitrobenzimidazol-2-ylthio)methyl]-2,3,4-trihydronaphthalen-1-one(Compound 125)

[1368] According to the method of 5108,5-nitro-1H-benzoimidazole-2-thiol (195 mg, 1.0 mmol, 1.0 M in THF) iscombined with the product from Example 65, step 1 (100 mg, 0.198 mmol,0.10 M in THF/acetonitrile (1:1)) to afford 4 mg of the desired sulfide(Compound 125) as a tan glass. Low resolution mass spectrum (LC-MS,APCI) m/z 539 [M+H]⁺.

EXAMPLE 126

[1369] Synthesis of2-{[2-((1S)-2-Imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]methylthio}pyridine-3-carboxylicacid (Compound 126)

[1370] According to the method of Example 108, 2-mercaptonicotinic acid(155 mg, 1.0 mmol, 1.0 M in THF) is combined with the product fromExample 65, step 1 (100 mg, 0.198 mmol, 0.10 M in THF/acetonitrile(1:1)) to afford 38 mg of the desired sulfide (Compound 126) as a tanglass. Low resolution mass spectrum (LC-MS, APCI) m/z 499 [M+H]⁺.

EXAMPLE 127

[1371] Synthesis of6-((1S)-2-Imidazolyl-phenylethoxy)-5-[(1-methyl(1,2,3,4-tetraazol-5-ylthio))methyl]-2,3,4-trihydronaphthalen-1-one(Compound 127)

[1372] According to the method of Example 108,1-methyl-1H-tetrazole-5-thiol (116 mg, 1.0 mmol, 1.0 M in THF) iscombined with the product from Example 65, step 1 (100 mg, 0.198 mmol,0.10 M in THF/acetonitrile (1:1)) to afford 49 mg of the desired sulfide(Compound 127) as a tan glass. Low resolution mass spectrum (LC-MS,APCI) m/z 460 [M+H]⁺.

EXAMPLE 128

[1373] Synthesis of6-((1S)-2-Imidazol-2]-1-phenylethoxy)-5-[(2,2,2-trifluoroethylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 128)

[1374] According to the method of Example 108,2,2,2-trifluoroethanethiol (116 mg, 1.0 mmol, 1.0 M in THF) is combinedwith the product from Example 65, step 1 (100 mg, 0.198 mmol, 0.10 M inTHF/acetonitrile (1:1)) to afford 24 mg of the desired sulfide (Compound128) as a tan glass. Low resolution mass spectrum (LC-MS, APCI) m/z 460[M+H]⁺.

EXAMPLE 129

[1375] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-naphthylthiomethyl)-2,3,4-trihydronaphthalen-1-one(Compound 129)

[1376] According to the method of Example 108, naphthalen-2-thiol (160mg, 1.0 mmol, 1.0 M in THF) is combined with the product from Example65, step 1 (100 mg, 0.198 mmol, 0.10 M in THF/acetonitrile (1:1)) toafford 9 mg of the desired sulfide (Compound 129) as a tan glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 504 [M+H]⁺.

EXAMPLE 130

[1377] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-bromophenylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 130)

[1378] According to the method of Example 108, 2-bromobenzenethiol (189mg, 1.0 mmol, 1.0 M in THF) is combined with the product from Example65, step 1 (100 mg, 0.198 mmol, 0.10 M in THF/acetonitrile (1:1)) toafford 36 mg of the desired sulfide (Compound 130) as a tan glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 532 [M+H]⁺.

EXAMPLE 131

[1379] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-chlorophenylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 131)

[1380] According to the method of Example 108, 2-chlorobenzenethiol (144mg, 1.0 mmol, 1.0 M in THF) is combined with the product from Example65, step 1 (100 mg, 0.198 mmol, 0.10 M in THF/acetonitrile (1:1)) toafford 40 mg of the desired sulfide (Compound 131) as a tan glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 488 [M+H]⁺.

EXAMPLE 132

[1381] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2,6-dichlorophenylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 132)

[1382] According to the method of Example 108, 2,6-dichlorobenzenethiol(179 mg, 1.0 mmol, 1.0 M in THF) is combined with the product fromExample 65, step 1 (100 mg, 0.198 mmol, 0.10 M in THF/acetonitrile(1:1)) to afford 30 mg of the desired sulfide (Compound 132) as a tanglass. Low resolution mass spectrum (LC-MS, APCI) m/z 522 [M+H]⁺.

EXAMPLE 133

[1383] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-methoxyphenylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 133)

[1384] According to the method of Example 108, 2-methoxybenzenethiol(140 mg, 1.0 mmol, 1.0 M in THF) is combined with the product fromExample 65, step 1 (100 mg, 0.198 mmol, 0.10 M in THF/acetonitrile(1:1)) to afford 37 mg of the desired sulfide (Compound 133) as a tanglass. Low resolution mass spectrum (LC-MS, APCI) m/z 484 [M+H]⁺.

EXAMPLE 134

[1385] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-methylphenylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 134)

[1386] According to the method of Example 108, 2-methylbenzenethiol (124mg, 1.0 mmol, 1.0 M in THF) is combined with the product from Example65, step 1 (100 mg, 0.198 mmol, 0.10 M in THF/acetonitrile (1:1)) toafford 34 mg of the desired sulfide (Compound 134) as a tan glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 468 [M+H]⁺.

EXAMPLE 135

[1387] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-methoxyphenylthio)methyl-2,3,4-trihydronaphthalen-1-one (Compound 135)

[1388] According to the method of Example 108, 4-methoxybenzenethiol(140 mg, 1.0 mmol, 1.0 M in THF) is combined with the product fromExample 65, step 1 (100 mg, 0.198 mmol, 0.10 M in THF/acetonitrile(1:1)) to afford 44 mg of the desired sulfide (Compound 135) as a tanglass. Low resolution mass spectrum (LC-MS, APCI) m/z 484 [M+H]⁺.

EXAMPLE 136

[1389] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-methyl(1,2,4-triazol-3-ylthio))methyl]-2,3,4-trihydronaphthalen-1-one(Compound 136)

[1390] According to the method of Example 108,4-methyl-4H-[1,2,4]triazole-3-thiol (115 mg, 1.0 mmol, 1.0 M in THF) iscombined with the product from Example 65, step 1 (100 mg, 0.198 mmol,0.10 M in THF/acetonitrile (1:1)) to afford 21 mg of the desired sulfide(Compound 136) as a tan glass. Low resolution mass spectrum (LC-MS,APCI) m/z 459 [M+H]⁺.

EXAMPLE 137

[1391] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-nitrophenylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 137)

[1392] According to the method of Example 108, 4-nitro-benzenethiol (155mg, 1.0 mmol, 1.0 M in THF) is combined with the product from Example65, step 1 (100 mg, 0.198 mmol, 0.10 M in THF/acetonitrile (1:1)) toafford 42 mg of the desired sulfide (Compound 137) as a tan glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 499 [M+H]⁺.

EXAMPLE 138

[1393] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(3-methoxyphenylthio)methyl]-2,3,4-trihydronaphthalen-4-1-one (Compound 138)

[1394] According to the method of Example 108, 3-methoxybenzenethiol(140 mg, 1.0 mmol, 1.0 M in THF) is combined with the product fromExample 65, step 1 (100 mg, 0.198 mmol, 0.10 M in THF/acetonitrile(1:1)) to afford 48 mg of the desired sulfide (Compound 138) as a tanglass. Low resolution mass spectrum (LC-MS, APCI) m/z 484 [M+H]⁺.

EXAMPLE 139

[1395] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-chlorophenylthio)methyl]-2,3,4-trihydronaphthalen-1-one (Compound 139)

[1396] According to the method of Example 108, 4-chlorobenzenethiol (144mg, 1.0 mmol, 1.0 M in THF) is combined with the product from Example65, step 1 (100 mg, 0.198 mmol, 0.10 M in THF/acetonitrile (1:1)) toafford 5 mg of the desired sulfide (Compound 139) as a tan glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 488 [M+H]⁺.

EXAMPLE 140

[1397] Synthesis of6-((1S)-2-Imidazolyl-1-phenylethoxy-5-(2-quinolylthiomethyl)-2,3,4-trihydronaphthalen-1-one(Compound 140)

[1398] According to the method of Example 108, quinoline-2-thiol (161mg, 1.0 mmol, 1.0 M in THF) is combined with the product from Example65, step 1 (100 mg, 0.198 mmol, 0.10 M in THF/acetonitrile (1:1)) toafford 41 mg of the desired sulfide (Compound 140) as a tan glass. Lowresolution mass spectrum (LC-MS, APCI) m/z 505 [M+H]⁺.

EXAMPLE 141

[1399]

[1400] Synthesis of6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(4-methoxy-benzenesulfinylmethyl)-3,4-dihydro-2H-napthalen-1-one(Compound 141)

[1401] 1.6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(4-methoxy-phenylsulfanylmethyl)-3,4-dihydro-2H-napthalen-1-one

[1402] To a solution of5-Bromomethyl-6-(2-imidazol-1-yl-1-phenyl-ethoxy)-3,3-dihydro-2H-napthalen-1-one,example 65 step 1 (100 mg, 0.198 mmol) in 1:1 anhydroustetrahydrofuran/acetonitrile (2 ml) was added the 4-methoxybenzene thiol(140 mg, 1.0 mmol, 1.0M in THF). The mixture was stirred for 18 hours at60° C. After cooling to room temperature, the solvent was removed andethyl acetate (3 ml) was added. The mixture was extracted sequentiallywith 2 N NaOH, (2×), and brine, (2×). The organic layer was dried overNa₂SO₄, and the solvent removed in vacuo to give 18.9 mg of the desiredsulfide as a tan glass. 18.9 mg, 20% yield. MS LC-MS, APCI m/z 485[M+H]⁺.

[1403] 2.6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(4-methoxy-benzenesulfinylmethyl)-3,4-dihydro-2H-napthalen-1-one

[1404] To the above product was added Davis oxiziridine reagent, whichis 2-Benzensulfonyl-3-phenyloxaziridine (26 mg, 0.1 mmole) in chloroform(2 ml). After stirring for 18 hr at room temperature, the solvent wasremoved in vacuo. The material was purified by reversed-phase HPLC (0.1%trifluoroacetic acid in acetonitrile and 0.1% aqueous trifluoroaceticacid as eluent; C-18 column) to give 3 mg of the desired product(Compound 141) as a colorless solid. LC-MS, APCI m/z 501 [M+H]⁺.

EXAMPLE 142

[1405]

[1406] Synthesis of(±)-6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(pyridine-2-sulfinylmethyl)-3,4-dihydro-2H-napthalen-1-one(Compound 142)

[1407] The title compound was prepared according to the procedure forexample 141 steps 1,2 using5-Bromomethyl-6-(2-imidazol-1-yl-1-phenyl-ethoxy)-3,3-dihydro-2H-napthalen-1-oneexample 65 step 1, and pyridine-2-thiol. LC-MS, APCI m/z 472 [M+H]⁺.

EXAMPLE 143

[1408]

[1409] Synthesis of(±)-6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(propane-2-sulfinylmethyl)-3,4-dihydro-2H-napthalen-1-one(Compound 143)

[1410] The title compound was prepared according to the procedure forexample 141 steps 1,2 using5-Bromomethyl-6-(2-imidazol-1-yl-1-phenyl-ethoxy)-3,3-dihydro-2H-napthalen-1-oneexample 65 step 1, and propane-2-thiol. LC-MS, APCI m/z 437 [M+H]⁺.

EXAMPLE 144

[1411]

[1412] Synthesis ofN-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-N-β-tolyl-acetamide(Compound 144)

[1413] To a solution of N-β-Tolyl-acetamide (149 mg, 0.1 mmol) in 10:1anhydrous THF/DMF (15 ml) was added NaH, 95%, (50 mg, 2 mmol) at 0° C.After stirring for 30 min, a solution of5-Bromomethyl-6-(2-imidazol-1-yl-1-phenyl-ethoxy)-3,3-dihydro-2H-napthalen-1-one,example 65, step 1 (505 mg, 1 mmol) in 1:1 THF/DMF (5 ml) andtriethylamine (101 mg, 1 mmol) was added. The mixture was stirred for 18hr at room temperature. The reaction mixture was diluted up to 25 mlwith 2 N NaOH and extracted with ethyl acetate, 3×10 ml. The organicswere combined, washed with brine, dried over anhydrous magnesium sulfateand evaporated in vacuo. The material was purified by chromatography on10 g of MP-TsOH (macroporous polystyrene sulfonic acid) eluted with amethanol. 27 mg, 5.5% Yield. LC-MS, APCI m/z 494 [M+H]⁺.

EXAMPLE 145

[1414]

[1415] Synthesis of6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-[1H-indazol-5-ylamino)methyl]-3,4-dihydro-2H-napthalen-one(Compound 145)

[1416] A solution of5-Bromomethyl-6-(2-imidazol-1-yl-1-phenyl-ethoxy)-3,3-dihydro-2H-napthalen-1-one,example 65, step 1 (100 mg, 0.198 mmol) in 1:1 anhydroustetrahydrofuran/acetonitrile (2 ml) was dispensed into a 16×20 mm screwcap vial. To this mixture was added 0.75 ml of 0.4 M1H-indazol-5-ylamine solution in acetonitrile (0.3 mmol). The mixturewas shaken for 1 hour at 50° C. After cooling to room temperature, 2 mlof 2 N NaOH was added. The mixture was extracted with ethyl acetate 3×2ml. The organic layers were combined, washed with brine (2 ml), dried(Na₂SO₄), and the solvent removed in vacuo. The material was purified bychromatography on 10 g of Zorbax C-18, eluted with a gradient of 20 to80% water/acetonitrile to afford 18 mg of the desired product LC-MS,APCI m/z 478 [M+H]⁺.

EXAMPLE 146

[1417]

[1418] Synthesis of6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(4-phenyl-piperazin-1-ylmethyl)-3,4-dihydro-2H-napthalen-1-one(Compound 146)

[1419] The title compound was prepared according to the procedure forexample 145 using5-bromomethyl-6-(2-imidazol-1-yl-1-phenyl-ethoxy)-3,3-dihydro-2H-napthalen-1-one,example 65 step 1, and 1-phenyl-piperazine to afford 8 mg of the desiredproduct. LC-MS, APCI m/z 507 [M+H]⁺.

EXAMPLE 147

[1420]

[1421] Synthesis of6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(4-pyridin-2-yl-piperazin-1-ylmethyl)-3,4-dihydro-2H-napthalen-1-one(Compound 147)

[1422] The title compound was prepared according to the procedure forexample 145 using5-bromomethyl-6-(2-imidazol-1-yl-1-phenyl-ethoxy)-3,3-dihydro-2H-napthalen-1-one,example 65 step 1 and 1-pyridin-2-yl-piperazine to afford 40 mg of thedesired product. LC-MS, APCI m/z 508 [M+H]⁺.

EXAMPLE 148

[1423]

[1424] Synthesis of6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(quinolin-8-ylaminomethyl)-3,4-dihydro-2H-napthalen-1-one(Compound 148)

[1425] The title compound was prepared according to the procedure forexample 145 using5-bromomethyl-6-(2-imidazol-1-yl-1-phenyl-ethoxy)-3,3-dihydro-2H-napthalen-1-one,example 65 step 1 and quinolin-8-ylamine to afford 20 mg of the desiredproduct. LC-MS, APCI m/z 489 [M+H]⁺.

EXAMPLE 149

[1426]

[1427] Synthesis of2-{[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-napthalen-1-ylmethyl]-amino}-benzonitrile(Compound 149)

[1428] The title compound was prepared according to the procedure forexample 145 using5-bromomethyl-6-(2-imidazol-1-yl-1-phenyl-ethoxy)-3,3-dihydro-2H-napthalen-1-one,example 65 step 1 and 2-amino-benzonitrile to afford 22 mg of thedesired product LC-MS, APCI m/z 463 [M+H]⁺.

EXAMPLE 150

[1429]

[1430] Synthesis of5-[(4-Fluoro-phenylamino)-methyl]-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one(Compound 150)

[1431] The title compound was prepared according to the procedure forexample 145 using5-bromomethyl-6-(2-imidazol-1-yl-1-phenyl-ethoxy)-3,3-dihydro-2H-napthalen-1-one,example 65 step 1 and 4-bromo-phenylamine to afford 36 mg of the desiredproduct LC-MS, APCI m/z 516 [M]⁺.

EXAMPLE 151

[1432]

[1433] Synthesis of5-[(4-Fluoro-phenylamino)-methyl]-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one(Compound 151)

[1434] The title compound was prepared according to the procedure forexample 145 using5-bromomethyl-6-(2-imidazol-1-yl-1-phenyl-ethoxy)-3,3-dihydro-2H-napthalen-1-one,example 65 step 1 and 4-fluoro-phenylamine to afford 25 mg of thedesired product LC-MS, APCI m/z 456 [M+H]⁺.

EXAMPLE 152

[1435]

[1436] Synthesis of5-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylamino)-methyl]-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one(Compound 152)

[1437] The title compound was prepared according to the procedure forexample 145 using5-bromomethyl-6-(2-imidazol-1-yl-1-phenyl-ethoxy)-3,3-dihydro-2H-napthalen-1-one,example 65 step 1 and 2,3-dihydro-benzo[1,4]dioxin-6-ylamine to afford18 mg of the desired product. LC-MS, APCI m/z 496 [M+H]⁺.

EXAMPLE 153

[1438]

[1439] Synthesis of5-(304-Dichloro-benzylsulfanylmethyl)-6-((1S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one(Compound 153)

[1440] 1.5-(3,4-Dichloro-benzylsulfanylmethyl)-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one

[1441] 5-Chloromethyl-6-hydroxy-1-tetralone (315 mg, 1.5 mmol) and(3,4-Dichloro-phenyl)-methanethiol (1.0 mL, 6.0 mmol) were sealed in a16×120 mm screw capped tube and heated to 40° C. overnight. The excess(3,4-Dichloro-phenyl)methanethiol was removed in vacuo and the residuewas purified by silica gel chromatography (hexanes/ethyl acetate/aceticacid, 58:40:2) to give 350 mg (63%) of the desired product as a tanpowder: (LC-MS, APCI) m/z 367/369 [M+H]⁺.

[1442] 2.5-(3,4-Dichloro-benzylsulfanylmethyl)-6-((1S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one

[1443]5-(3,4-Dichloro-benzylsulfanylmethyl)-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one(256 mg, 0.69 mmol), (R)-2-imidazol-1-yl-1-phenyl-ethanol (144 mg, 0.75mmol), and triphenylphosphine resin (1.46 g, loading 1.41 mmol/g) werecombined in dry tetrahydrofuran (10 mL) and treated with diisopropylazodicarboxylate (271 μL, 2.0 mmol). The resulting orange-brownheterogeneous mixture was allowed to stir at ambient temperatureovernight. The spent triphenylphosphine resin was removed by filtration,washing sequentially with ethyl acetate, methanol, and chloroform. Thefiltrate was concentrated in vacuo and the crude material was purifiedby silica gel chromatography (hexanes/ethyl acetate/triethylamine28:70:2) to give 280 mg (75%) of the desired product as a colorlesssolid: (LC-MS, APCI) m/z 553/555 [M+H]⁺.

[1444] 3.6-(2-Imidazol-1-yl-1-phenyl-ethoxy)-5-{[2-(pyridin-4-yloxy)-ethylamino]-methyl}-3,4-dihydro-2H-naphthalen-1-one

[1445] 2-(Pyridin-4-yloxy)-ethylamine (1.0 mL, 0.4 mmol, 0.4 M inμ,μ,μ-trifluorotoluene) and6-((1S)-2-imidazoyl-1-phenylethoxy)-5-(bromomethyl)-2,3,4-trihydronapthalen-1-one(Example 65, step 1)(100 mg, 0.198 mmol) were sealed in a 16×120 mmscrew capped tube and heated to 50° C. (45 min). Reaction mixture wascooled to rt and partitioned between 2N sodium hydroxide and ethylacetate. The organic layer was separated, washed (brine), dried(Na₂SO₄), and concentrated in vacuo. The residue was purified by flashsilica gel chromatography (ethyl acetate/triethylamine/methanol, 17:2:1)to give 31 mg (32%) of the desired product as a colorless glass: (LC-MS,APCI) m/z 483 [M+H]⁺.

EXAMPLE 154

[1446]

[1447] Methyl2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoate(Compound 154)

[1448] 1. Methyl2-(2-hydroxy-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methylsulfanylbenzoate.

[1449] To a stirred mixture of5-chloromethyl-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (6.29 g, 29.8mmol) and methyl thiosalicylate (5.0 g, 29.8 mmol) in dichloromethane(100 ml) was added triethylamine (9.0 ml). The mixture was furtherstirred at 22° C. under a nitrogen atmosphere and in the dark for 23 h.The volatiles were evaporated under reduced pressure to give a pinksolid which was triturated with methanol (30 ml). 0.1N HCl (100 ml) wasadded and acidified to pH=1 with conc HCl. The mixture was furtherstirred at room temperature for 3 h. The precipitate was filtered,washed with water and dried to give the desired product as a light pinksolid, 10.0 g, 98% yield; mp 203-205° C. (from MeOH). NMR spectrum wasconsistent with structure. Calcd. For: C₁₉H₁₈O₆S.0.5H₂O

[1450] Theory: C, 64.94; H, 5.45; S, 9.13.

[1451] Found: C, 65.28; H, 5.53; S, 9.52.

[1452] 2. Methyl2-(2-hydroxy-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methylsulfonylbenzoate

[1453] To a mixture of methyl2-(2-hydroxy-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methylsulfanylbenzoate(5.00 g, 14.6 mmol) in dichloromethane (200 ml) was added solid m-CPBA(8.92 g of a 70% pure sample, 36.6 mmol) portionwise while stirring at0° C. After 5 h at 0° C., DMSO (10 ml) was added and stirred for 10 min.Volatiles were removed under reduced pressure. The residue was treatedwith an excess of an aqueous solution of sodium bicarbonate and stirredat 0° C. for 30 min. The precipitate was filtered; washed with water;and dried to give a colorless solid, 4.70 g, 86% yield; mp 194-196° C.(from ethyl acetate). NMR spectrum was consistent with structure. Calcd.For: C₁₉H₁₈O₆S:

[1454] Theory: C, 60.95; H, 4.85; S, 8.56.

[1455] Found: C, 60.55; H, 5.10; S, 8.35.

[1456] 3. Methyl2-{[(2-{[((S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoate

[1457] To a stirred homogeneous mixture of methyl2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoate(1.98 g, 5.3 mmol), (R)-2-imidazol-1-yl-1 phenylethanol (1.00 g, 5.3mmol) and triphenylphosphine (2.10 g, 8.0 mmol) in THF (70 ml) under anitrogen atmosphere was added dropwise (over 25 min) a solution ofdiethyl azodicarboxylate (1.39 g, 8.0 mmol) in THF (30 ml). The reactionwas further stirred at room temperature (22° C.) for 66 h. Brine wasadded and the product was extracted into ethyl acetate. The ethylacetate solution was evaporated and the crude product was purified by asilica gel column, using ethyl acetate to remove the non-polarimpurities and dichloromethane-methanol (10:1) to elute the requiredcompound as a colorless solid, 2.62 g, 91% yield; mp 212° C. (from ethylacetate-MeOH). NMR spectrum was consistent with structure. Calcd. For:C₃₀H₂₈N₂O₆S.0.5H₂O:

[1458] Theory: C, 65.08; H, 5.28; N, 5.06.

[1459] Found: C, 65.21; H, 5.12; N, 4.90

EXAMPLE 155

[1460]

[1461] Methyl4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoate(Compound 155)

[1462] 1. Methyl4-(2-hydroxy-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoate

[1463] Using the method in Example 154, this compound was prepared from5-chloromethyl-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (6.29 g, 29.8mmol) and methyl 4-mercaptobenzoate (5.00 g, 29.8 mmol) to give thedesired compound as a coilorless solid, 9.96 g, 98% yield, mp 191-192°C. (from dicloromethane-MeOH). NMR spectrum was consistent withstructure. Calcd. For C₁₉H₁₈O₄S:

[1464] Theory: C, 66.65; H, 5.30.

[1465] Found: C, 66.84; H, 5.38.

[1466] 2. Methyl4-(2-hydroxy-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methylsulfonylbenzoate

[1467] Using the method in Example 154 this compound was prepared frommethyl4-(2-hydroxy-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methylsulfanylbenzoate(5.00 g, 14.6 mmol) and m-CPBA (8.92 g of a 70% pure sample, 36.6 mmol)as a colorless solid, 5.09 g, 93% yield; mp 132-134° C. (from ethylacetate). NMR spectrum was consistent with structure. Calcd. ForC₁₉H₁₈O₆S.0.5H₂O:

[1468] Theory: C, 60.95; H, 4.85.

[1469] Found: C, 59.13; H, 5.18.

[1470] 3. Methyl4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoate

[1471] Using the method in Example 154, this compound was prepared frommethyl4-(2-hydroxy-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methylsulfonylbenzoate(1.98 g, 5.3 mmol), (R)-2-imidazol-1-yl-1-phenylethanol (1.00 g, 5.3mmol), Ph₃P (2.10 g, 8.0 mmol), and diethyl azodicarboxylate (1.39 g,8.0 mmol) as a solid-foam, 2.78 g, 96% yield; mp 105° C. NMR spectrumwas consistent with structure. Calcd. For C₃₀H₂₈N₂O₆S.H₂O:

[1472] Theory: C, 64.04; H, 5.37; N, 4.98.

[1473] Found: C, 64.33; H, 5.19; N, 5.32.

EXAMPLE 156

[1474]

[1475] Methyl4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoate(Compound 156)

[1476] 1. Methyl3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoate

[1477] Using the method in Example 154, this compound was prepared from5-chloromethyl-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (6.16 g, 29.2mmol) and methyl 3-mercaptobenzoate (4.90 g, 29.2 mmol) to give thedesired compound as a pale pink solid, 9.31 g, 93% yield, mp 93-95° C.(from ethyl acetate). NMR spectrum was consistent with structure. Calcd.For C₁₉H₁₈O₄S:

[1478] Theory: C, 66.65; H, 5.30.

[1479] Found: C, 66.43; H, 5.56.

[1480] 2. Methyl3-(2-hydroxy-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methylsulfonylbenzoate

[1481] Using the method in Example 154 this compound was prepared frommethyl3-(2-hydroxy-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methylsulfanylbenzoate(5.00 g, 14.6 mmol) and m-CPBA (8.92 g of a 70% pure sample, 36.6 mmol)as a colorless solid, 5.13 g, 94% yield; mp 230-232° C. (fromdichloromethane-MeOH). NMR spectrum was consistent with structure.Calcd. For C₁₉H₁₈O₆S:

[1482] Theory: C, 60.95; H, 4.85.

[1483] Found: C, 61.09; H, 4.98.

[1484] 3. Methyl3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoate

[1485] Using the method in Example 154, this compound was prepared frommethyl3-(2-hydroxy-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methylsulfonylbenzoate(1.98 g, 5.3 mmol), (R)-2-imidazol-1-yl-1-phenylethanol (1.00 g, 5.3mmol), Ph₃P (2.10 g, 8.0 mmol), and diethyl azodicarboxylate (1.39 g,8.0 mmol) as a solid-foam, 2.80 g, 96% yield; mp 85° C. NMR spectrum wasconsistent with structure. Calcd. For C₃₀H₂₈N₂O₆S.0.5H₂O:

[1486] Theory: C, 65.08; H, 5.28; N, 5.06.

[1487] Found: C, 65.22; H, 5.23; N, 5.17.

EXAMPLE 157

[1488]

[1489] Methyl4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoate(Compound 157)

[1490] Using method in Example 154, this compound was prepared frommethyl4-(2-hydroxy-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methylsulfanylbenzoate(1.81 g, 5.3 mmol), (R)-2-imidazol-1-yl-1-phenylethanol (1.00 g, 5.3mmol), Ph₃P (2.10 g, 8.0 mmol), and diethyl azodicarboxylate (1.39 g,8.0 mmol) and purified by a silica-column (eluting withdichloromethane-MeOH 20:1) as a solid-foam, 2.70 g, 99% yield; mp 75° C.NMR spectrum was consistent with structure. Calcd. For C₃₀H₂₈N₂O₄S.H₂O:

[1491] Theory: C, 67.90; H, 5.70; N, 5.28.

[1492] Found: C, 68.31; H, 5.46; N, 5.68.

EXAMPLE 158

[1493]

[1494] Methyl3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoate(Compound 158)

[1495] Using the method in Example 154, this compound was prepared frommethyl3-(2-hydroxy-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methylsulfanylbenzoate(1.81 g, 5.3 mmol), (R)-2-imidazol-1-yl-1-phenylethanol (1.00 g, 5.3mmol), Ph₃P (2.10 g, 8.0 mmol), and diethyl azodicarboxylate (1.39 g,8.0 mmol) and purified by a silica-column (eluting withdichloromethane-MeOH 20:1) as a solid-foam, 2.56 g, 94% yield; mp 65° C.NMR spectrum was consistent with structure. Calcd. ForC₃₀H₂₈N₂O₄S.0.5H₂O:

[1496] Theory: C, 69.08; H, 5.60; N, 5.37.

[1497] Found: C, 69.08; H, 5.55; N, 5.67

EXAMPLE 159

[1498]

[1499]2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicAcid. (Compound 159)

[1500] A mixture of methyl2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoate(2.47 g, 4.54 mmol), 2N lithium hydroxide (9.1 ml), p-dioxane (45 ml)and water (27 ml) was stirred at room temperature for 2 h. Water (200ml) was added and acidified with conc HCl to pH 3 at 0° C. Aqueous NaCl(50 ml) was added and further stirred at 0° C. for 1H. The precipitatewas filtered, washed with water, and dried, to give a beige solid, 1.88g, 78% yield; mp 230° C. (from dichloromethane-MeOH). NMR spectrum wasconsistent with structure. Calcd. For C₂₉H₂₆N₂O₆S.H₂O: Theory: C, 63.49;H, 5.14; N, 5.11. Found: C, 63.53; H, 5.08; N, 4.99.

EXAMPLE 160

[1501]

[1502]4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicAcid. (Compound 160)

[1503] Using the method for Example 159, this compound was prepared frommethyl4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoate(2.32 g, 4.27 mmol) as a pale yellow solid, 1.82 g, 81% yield, mp 250°C. NMR was consistent with structure.

[1504] Calcd. For C₂₉H₂₆N₂O₆S.1.5H₂O:

[1505] Theory: C, 62.47; H, 5.24; N, 5.02.

[1506] Found: C, 62.45; H, 5.38; N, 5.16.

EXAMPLE 161

[1507]

[1508]3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicAcid. (Compound 161)

[1509] Using the method for Example 159, this compound was prepared frommethyl3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoate(2.36 g, 4.34 mmol) as a beige solid, 2.18 g, 95% yield, mp 236-238° C.NMR was consistent with structure. Calcd. For C₂₉H₂₆N₂O₆S.H₂O:

[1510] Theory: C, 63.49; H, 5.14; N, 5.11.

[1511] Found: C, 63.46; H, 5.07; N, 5.16.

EXAMPLE 162

[1512]

[1513]4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicAcid. (Compound 162)

[1514] Using the method for Example 159, this compound was prepared frommethyl4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoate(2.29 g, 4.47 mmol) as a beige solid, 2.20 g, 98% yield, mp 215° C. NMRwas consistent with structure. Calcd. For C₂₉H₂₆N₂O₄S.0.5H₂O:

[1515] Theory: C, 68.62; H, 5.36; N, 5.52.

[1516] Found: C, 68.74; H, 5.52; N, 5.93.

EXAMPLE 163

[1517]

[1518]3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicAcid. (Compound 163)

[1519] Using the method for Example 159, this compound was prepared frommethyl3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoate(2.12 g, 4.14 mmol) as a beige solid, 2.04 g, 99% yield, mp 225° C. NMRwas consistent with structure. Calcd. For C₂₉H₂₆N₂O₄S.0.5H₂O:

[1520] Theory: C, 68.62; H, 5.36; N, 5.52.

[1521] Found: C, 68.88; H, 5.22; N, 5.47.

EXAMPLE 164

[1522]

[1523]2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl)-N-methylbenzamide.(Compound 164)

[1524] A mixture of2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid. (159 mg, 0.30 mmol) and 1,1′-carbonyldiimidazole (73 mg, 0.45mmol) in DMF (2 ml) was stirred at 50° C.(bath) for 10 min.Triethylamine (0.21 ml, 1.50 mmol) and methylamine hydrochloride (61 mg,0.90 mmol) were added. The reaction mixture was stirred at roomtemperature for 24 h. Water (15 ml) was added and stirred at 0° C. for30 min. The precipitate was filtered, washed with water, and dried togive a crude product which was recrystalized from ethyl acetate-MeOH toafford the required compound as a light brown solid, 85 mg, 52% yield;mp 249-251° C. NMR was consistent with the structure. Calcd. ForC₃₀H₂₉N₃O₅S:

[1525] Theory: C, 66.28; H, 5.38; N, 7.73.

[1526] Found: C, 65.97; H, 5.50; N, 7.57.

EXAMPLE 165

[1527]

[1528]N-(2-Hydroxyethyl)-2-{[(2-{[(1S)-2-(1H-imidazol-Z-yl)-1-phenylethyl]oxy}-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 165)

[1529] Using the method for Example 164, this compound was prepared from2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (159 mg, 0.30 mmol) and 2-aminoethanol (92 mg, 1.50 mmol). Thereaction product was extracted into ethyl acetate and purified by asilica column (eluted with dichloromethane-MeOH 20:1) to give a paleyellow solid, 100 mg, 58% yield; mp 241-243° C. (from ethylacetate-MeOH). NMR was consistent with the structure. Calcd. ForC_(31H31)N₃0₆S

[1530] Theory: C, 64.91; H, 5.45; N, 7.32.

[1531] Found: C, 64.66; H, 5.56; N, 7.23.

EXAMPLE 166

[1532]

[1533]N-4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoyl-β-alanine.(Compound 166)

[1534] To a solution of ethyl3-[(4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoyl)amino]propanoate(370 mg, 0.588 mmol) in a mixed solvent of water (6 ml) and p-dioxane (6ml) was added 2N LiOH (1.2 ml, 2.35 mmol). The reaction mixture wasstirred at room temperature for 2 h. Brine (30 ml) was added and the pHadjusted to 6 by addition of conc HCl. The resulting mixture wasconcentrated under pressure at 35° C. (bath). It was stood at 0° C. forseveral hours. The precipitate was filtered, washed with cold water anddried to give the desired acid as a light brown solid, 220 mg, 62%yield; mp 220° C. NMR spectrum was consistent with the structure. Calcd.For C₃₂H₃₁N₃O₇S.2H₂O:

[1535] Theory: C, 60.27; H, 5.53; N, 6.59.

[1536] Found: C, 60.81; H, 5.48; N, 6.74

EXAMPLE 167

[1537]

[1538]N-2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoyl-β-alanine.(Compound 167)

[1539] Using method for Example 166, this acid was prepared from ethyl3-[(2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoyl)amino]propanoate(400 mg, 0.636 mmol) as a beige solid, 260 mg, 68% yield; mp 215° C. NMRspectrum was consistent the structure. Calcd. For C₃₂H₃₁N₃O₇S.2H₂O:

[1540] Theory: C, 60.27; H, 5.53; N, 6.59.

[1541] Found: C, 60.41; H, 5.56; N, 6.40.

EXAMPLE 168

[1542]

[1543]N-3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoyl-β-alanine.(Compound 168)

[1544] Using the method for Example 166, this acid was prepared fromethyl3-[(3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoyl)amino]propanoate(400 mg, 0.636 mmol) as a colorless solid, 230 mg, 60% yield; mp 220° C.NMR spectrum was consistent the structure. Calcd. For C₃₂H₃₁N₃O₇S.2H₂O:

[1545] Theory: C, 60.27; H, 5.53; N, 6.59.

[1546] Found: C, 59.92; H, 5.24; N, 6.43

EXAMPLE 169

[1547]

[1548]N-2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoyl-β-alanine.(Compound 169)

[1549] Using the method for Example 166, this acid was prepared fromethyl3-[(3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoyl)amino]propanoate(380 mg, 0.636 mmol) as a colorless solid, 230 mg, 64% yield; mp 230° C.NMR spectrum was consistent the structure. Calcd. ForC₃₂H₃₁N₃O₅S.2.5H₂O:

[1550] Theory: C, 62.53; H, 5.90; N, 6.84.

[1551] Found: C, 62.47; H, 5.43; N, 6.92

EXAMPLE 170

[1552]

[1553] N-4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-S,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoyl-β-alanine.(Compound 170)

[1554] Using the method for Example 166, this acid was prepared fromethyl3-[(4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoyl)amino]propanoate(380 mg, 0.636 mmol) as a beige solid, 230 mg, 64% yield; mp 240° C. NMRspectrum was consistent with the structure. Calcd. ForC₃₂H₃₁N₃O₅S.1.5H₂O:

[1555] Theory: C, 64.41; H, 5.74; N, 7.04.

[1556] Found: C, 64.32; H, 5.62; N, 7.17

EXAMPLE 171

[1557]

[1558]N-3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoyl-β-alanine.(Compound 171)

[1559] Using method for Example 166, this acid was prepared from ethyl3-[(3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoyl)amino]propanoate(380 mg, 0.636 mmol) as a beige solid, 270 mg, 75% yield; mp 235° C. NMRspectrum was with consistent the structure. Calcd. ForC₃₂H₃₁N₃O₅S.1.5H₂O:

[1560] Theory: C, 64.41; H, 5.74; N, 7.04.

[1561] Found: C, 64.34; H, 5.31; N, 6.95.

EXAMPLE 172

[1562]N-(2-Hydroxyethyl)-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 172)

[1563] A mixture of 1,1′-carbonyldiimidazole (49 mg, 0.30 mmol, 0.60M inDMF) and3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) in a capped vial were placed in aheater-shaker at 55° C. for 20 min. It was removed from theheater-shaker and stood at room temperature. A solution of2-aminoethanol (31 mg, 0.50 mmol, 1.0M in DMF) was added and thereaction mixture was further shaken at room temperature over-night.Water (6 ml) was added and the mixture was shaken at room temperaturefor 10 min. before being stored in refrigerator over-night. Theprecipitate was filtered, washed with cold water (2×0.5 ml) and dried ina vacuum oven at 40° C. until constant weight was obtained. 44 mg of therequired benzamide was obtained as a beige solid: Low resolution massspectrum (LC-MS, APCI) m/z 542 [M+H]⁺.

EXAMPLE 173

[1564]N-(2-Hydroxyethyl)-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 173)

[1565] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and 2-aminoethanol (31 mg, 0.50mmol, 1.0M in DMF) were combined to give 30 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 542 [M+H]⁺.

EXAMPLE 174

[1566]N-(2-Hydroxyethyl)-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 174)

[1567] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and 2-aminoethanol (31 mg, 0.50mmol, 1.0M in DMF) were combined to give 45 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 542 [M+H]⁺.

EXAMPLE 175

[1568]N-(2-Hydroxyethyl)-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 175)

[1569] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and 2-aminoethanol (31 mg, 0.50mmol, 1.0M in DMF) were combined to give 27 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 574 [M+H]⁺.

EXAMPLE 176

[1570]N-(2-Hydroxyethyl)-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-4-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 176)

[1571] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and 2-aminoethanol (31 mg,0.50 mmol, 1.0M in DMF) were combined to give 28 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 574 [M+H]⁺.

EXAMPLE 177

[1572]N-[2-(Dimethylamino)ethyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 177)

[1573] Using the method in Example 172, 4-{[(2-{[(lS)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and 2-dimethylaminoethylamine (27mg, 0.30 mmol, 0.60M in DMF) were combined to give 50 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 569 [M+H]⁺.

EXAMPLE 178

[1574]N-[2-(Dimethylamino)ethyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 178)

[1575] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and 2-dimethylaminoethylamine (27mg, 0.30 mmol, 0.60M in DMF) were combined to give 46 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 569 [M+H]⁺.

EXAMPLE 179

[1576]N-[2-(Dimethylamino)ethyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 179)

[1577] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and 2-dimethylaminoethylamine (27mg, 0.30 mmol, 0.60M in DMF) were combined to give 27 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 569 [M+H]⁺.

EXAMPLE 180

[1578]N-[2-(Dimethylamino)ethyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 180)

[1579] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and 2-dimethylaminoethylamine (27mg, 0.30 mmol, 0.60M in DMF) were combined to give 20 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 601 [M+H]⁺.

EXAMPLE 181

[1580]N-[2-(Dimethylamino)ethyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 181)

[1581] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and 2-dimethylaminoethylamine (27mg, 0.30 mmol, 0.60M in DMF) were combined to give 26 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 601 [M+H]⁺.

EXAMPLE 182

[1582]N-[2-(Dimethylamino)ethyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Coompound 182)

[1583] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and 2-dimethylaminoethylamine (27mg, 0.30 mmol, 0.60M in DMF) were combined to give 15 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 601 [M+H]⁺.

EXAMPLE 183

[1584] Ethyl3-[(2-{[(2-{[(1S)-2-(1H-Imidazol-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoyl)amino]propanoate.(Compound 183)

[1585] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF), B-alanine ethyl esterhydrochloride (77 mg, 0.5 mmol, 1.0M in DMF) and triethylamine (51 mg,0.5 mmol, 1.0M in DMF) were combined to give 53 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 630 [M+H]⁺.

EXAMPLE 184

[1586] Ethyl4-[(2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoyl)amino]propanoate.(Compound 184)

[1587] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF), B-alanine ethyl esterhydrochloride (77 mg, 0.5 mmol, 1.0M in DMF) and triethylamine (51 mg,0.5 mmol, 1.0M in DMF) were combined to give 42 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 630 [M+H]⁺.

EXAMPLE 185

[1588] Ethyl27-[(2-{[(2-{[(S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoyl)amino]propanoate.(Compound 185)

[1589] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF), β-alanine ethyl esterhydrochloride (77 mg, 0.5 mmol, 1.0M in DMF) and triethylamine (51 mg,0.5 mmol, 1.0M in DMF) were combined to give 40 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 630 [M+H]⁺.

EXAMPLE 186

[1590] Ethyl2-[(2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoyl)amino]propanoate.(Compound 186)

[1591] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF), B-alanine ethyl esterhydrochloride (77 mg, 0.5 mmol, 1.0M in DMF) and triethylamine (51 mg,0.5 mmol, 1.0M in DMF) were combined to give 42 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 598 [M+H]⁺.

EXAMPLE 187

[1592] Ethyl3-[(2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoyl)aminopropanoate. (Compound 187)

[1593] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF), β-alanine ethylester hydrochloride (77 mg, 0.5 mmol, 1.0M in DMF) and triethylamine (51mg, 0.5 mmol, 1.0M in DMF) were combined to give 53 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 598 [M+H]⁺.

EXAMPLE 188

[1594] Ethyl4-[(2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoyl)amino]propanoate.(Compound 188)

[1595] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF), B-alanine ethyl esterhydrochloride (77 mg, 0.5 mmol, 1.0M in DMF) and triethylamine (51 mg,0.5 mmol, 1.0M in DMF) were combined to give 53 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 598 [M+H]⁺.

EXAMPLE 189

[1596]4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethoxy]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-methylbenzamide.(Compound 189)

[1597] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and a saturated solution ofmethylamine (1.0 ml in DMF) were combined to give 15 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 544 [M+H]⁺.

EXAMPLE 190

[1598]3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-methylbenzamide.(Compound 190)

[1599] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and a saturated solution ofmethylamine (1.0 ml in DMF) were combined to give 11 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 544 [M+H]⁺.

EXAMPLE 191

[1600]4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-methylbenzamide.(Compound 191)

[1601] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and a saturated solution ofmethylamine (1.0 ml in DMF) were combined to give 40 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 512 [M+H]⁺.

EXAMPLE 192

[1602]3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-naphthalenyl)methyl]sulfanyl}-N-methylbenzamide.(Compound 192)

[1603] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and a saturated solution ofmethylamine (1.0 ml in DMF) were combined to give 36 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 512 [M+H]⁺.

EXAMPLE 193

[1604]2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-methylbenzamide.(Compound 193)

[1605] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and a saturated solution ofmethylamine (1.0 ml in DMF) were combined to give 26 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 512 [M+H]⁺.

EXAMPLE 194

[1606]N-[(2R)-2-Hydroxypropyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 194)

[1607] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and (R)-1-amino-2-propanol (23 mg,0.30 mmol, 0.6M in DMF) were combined to give 32 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]⁺.

EXAMPLE 195

[1608]N-[(2R)-2-Hydroxypropyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 195)

[1609] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and (R)-1-amino-2-propanol (23 mg,0.30 mmol, 0.6M in DMF) were combined to give 48 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]⁺.

EXAMPLE 196

[1610]N-[(2S)-2-Hydroxypropyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 196)

[1611] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and (S)-1-amino-2-propanol (23 mg,0.30 mmol, 0.6M in DMF) were combined to give 48 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]⁺.

EXAMPLE 197

[1612]N-[(2S)-2-Hydroxypropyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 197)

[1613] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and (S)-1-amino-2-propanol (23 mg,0.30 mmol, 0.6M in DMF) were combined to give 52 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]⁺.

EXAMPLE 198

[1614]N-[(2S)-2-Hydroxypropyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 198)

[1615] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and (S)-1-amino-2-propanol (23 mg,0.30 mmol, 0.6M in DMF) were combined to give 37 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]⁺.

EXAMPLE 199

[1616]N-[(2S)-2-Hydroxypropyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 199)

[1617] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and (S)-1-amino-2-propanol (23 mg,0.30 mmol, 0.6M in DMF) were combined to give 32 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 588 [M+H]⁺.

EXAMPLE 200

[1618]N-[(2S)-2-Hydroxypropyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 200)

[1619] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and (S)-1-amino-2-propanol (23 mg,0.30 mmol, 0.6M in DMF) were combined to give 34 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 588 [M+H]⁺.

EXAMPLE 201

[1620]N-[(2S)-2-Hydroxypropyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-6-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 201)

[1621] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and (S)-1-amino-2-propanol (23 mg,0.30 mmol, 0.6M in DMF) were combined to give 23 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 588 [M+H]⁺.

EXAMPLE 202

[1622]N-[(2R)-2-Hydroxypropyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 202)

[1623] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and (R)-1-amino-2-propanol(23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 32 mg of thedesired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 588[M+H]⁺.

EXAMPLE 203

[1624]N-[(2R)-2-Hydroxpropyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 203)

[1625] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.110 mmol, 0.20M in DMF) and (R)-1-amino-2-propanol (23mg, 0.30 mmol, 0.6M in DMF) were combined to give 22 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 588 [M+H]⁺.

EXAMPLE 204

[1626]N-[(2R)-2-Hydroxypropyl]-3-{[(2-{[(1S)-2-(H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 204)

[1627] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and (R)-1-amino-2-propanol (23 mg,0.30 mmol, 0.6M in DMF) were combined to give 27 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 588 [M+H]⁺.

EXAMPLE 205

[1628]N-Ally-6-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 205)

[1629] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropene (17 mg, 0.30mmol, 0.6M in DMF were combined to give 44 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 570 [M+H]⁺.

EXAMPLE 206

[1630]N-Allyl-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 206)

[1631] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropene (17 mg, 0.30mmol, 0.6M in DMF) were combined to give 42 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 570 [M+H]⁺.

EXAMPLE 207

[1632]N-Allyl-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 207)

[1633] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropene (17 mg, 0.30mmol, 0.6M in DMF) were combined to give 38 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 570 [M+H]⁺.

EXAMPLE 208

[1634]N-Allyl-2-{[(2-{[(1S)-2-(1H-imidazol-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 208)

[1635] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropene (17 mg, 0.30mmol, 0.6M in DMF) were combined to give 46 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 538 [M+H]⁺.

EXAMPLE 209

[1636]N-Allyl-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 209)

[1637] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropene (17 mg, 0.30mmol, 0.6M in DMF) were combined to give 52 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 538 [M+H]⁺.

EXAMPLE 210

[1638]N-Allyl-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 210)

[1639] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropene (17 mg, 0.30mmol, 0.6M in DMF) were combined to give 48 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 538 [M+H]⁺.

EXAMPLE 211

[1640]2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-(2-propynyl)benzamide.(Compound 211)

[1641] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropyne (17 mg, 0.30mmol, 0.6M in DMF) were combined to give 45 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 536 [M+H]⁺.

EXAMPLE 212

[1642]4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-(2-propynyl)benzamide.(Compound 212)

[1643] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropyne (17 mg, 0.30mmol, 0.6M in DMF) were combined to give 54 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 536 [M+H]⁺.

EXAMPLE 213

[1644]3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-(2-propynyl)benzamide.(Compound 213)

[1645] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropyne (17 mg, 0.30mmol, 0.6M in DMF) were combined to give 49 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 536 [M+H]⁺.

EXAMPLE 214

[1646]4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-(2-propynyl)benzamide.(Compound 214)

[1647] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropyne (17 mg, 0.30mmol, 0.6M in DMF) were combined to give 44 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 568 [M+H]⁺.

EXAMPLE 215

[1648]3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-(2-propynyl)benzamide.(Compound 215)

[1649] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropyne (17 mg, 0.30mmol, 0.6M in DMF) were combined to give 40 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 568 [M+H]⁺.

EXAMPLE 216

[1650]2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-(2-propynyl)benzamide.(Compound 216)

[1651] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropyne (17 mg, 0.30mmol, 0.6M in DMF) were combined to give 38 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 568 [M+H]⁺.

EXAMPLE 217

[1652]N-Cyclopentyl-4-{[(2-{[(1S)-2-(H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)yl]ethyl]sulfonyl}benzamide.(Compound 217)

[1653] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and cyclopentylamine (26 mg, 0.30mmol, 0.6M in DMF) were combined to give 57 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 598 [M+H]⁺.

EXAMPLE 218

[1654]N-Cyclopentyl-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 218)

[1655] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and cyclopentylamine (26 mg, 0.30mmol, 0.6M in DMF) were combined to give 59 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 598 [M+H]⁺.

EXAMPLE 219

[1656]N-Cyclopentyl-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 219)

[1657] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and cyclopentylamine (26 mg, 0.30mmol, 0.6M in DMF) were combined to give 42 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 598 [M+H]⁺.

EXAMPLE 220

[1658]N-Cyclopentyl-4-{[(2-{[(S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 220)

[1659] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and cyclopentylamine (26 mg, 0.30mmol, 0.6M in DMF) were combined to give 51 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 566 [M+H]⁺.

EXAMPLE 221

[1660]N-Cyclopentyl-71-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 221)

[1661] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and cyclopentylamine (26 mg, 0.30mmol, 0.6M in DMF) were combined to give 48 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 566 [M+H]⁺.

EXAMPLE 222

[1662]N-Cyclopentyl-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 222)

[1663] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and cyclopentylamine (26 mg, 0.30mmol, 0.6M in DMF) were combined to give 47 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 566 [M+H]⁺.

EXAMPLE 223

[1664]N-Cyclopropyl-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 223)

[1665] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and cyclopropylamine (17 mg, 0.30mmol, 0.6M in DMF) were combined to give 41 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 570 [M+H]⁺.

EXAMPLE 224

[1666]N-Cyclopropyl-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 224)

[1667] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and cyclopropylamine (17 mg, 0.30mmol, 0.6M in DMF) were combined to give 44 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 570 [M+H]⁺.

EXAMPLE 225

[1668]N-Cyclopropyl-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 225)

[1669] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and cyclopropylamine (17 mg, 0.30mmol, 0.6M in DMF) were combined to give 42 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 570 [M+H]⁺.

EXAMPLE 226

[1670]N-Cyclopropyl-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 226)

[1671] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and cyclopropylamine (17 mg, 0.30mmol, 0.6M in DMF) were combined to give 47 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 538 [M+H]⁺.

EXAMPLE 227

[1672]N-Cyclopropyl-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 227)

[1673] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and cyclopropylamine (17 mg, 0.30mmol, 0.6M in DMF) were combined to give 52 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 538 [M+H]⁺.

EXAMPLE 228

[1674]N-Cyclopropyl-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 228)

[1675] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and cyclopropylamine (17 mg, 0.30mmol, 0.6M in DMF) were combined to give 43 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 538 [M+H]⁺.

EXAMPLE 229

[1676]N-(2-Furylmethyl)-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 229)

[1677] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and furfurylamine (29 mg, 0.30mmol, 0.6M in DMF) were combined to give 53 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 610 [M+H]⁺.

EXAMPLE 230

[1678]N-(2-Furylmethyl)-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 230)

[1679] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and furfurylamine (29 mg, 0.30mmol, 0.6M in DMF) were combined to give 55 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 610 [M+H]⁺.

EXAMPLE 231

[1680]N-(2-Furylmethyl)-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 231)

[1681] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and furfurylamine (29 mg, 0.30mmol, 0.6M in DMF) were combined to give 51 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 610 [M+H]⁺.

EXAMPLE 232

[1682]N-[2-Hydroxy-1-(hydroxymethyl)ethyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.

[1683] (Compound 232)

[1684] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and serinol (46 mg, 0.50mmol, 1.0M in DMF) were combined (reaction time 3 days at roomtemperature) to give 30 mg of the desired compound: Low resolution massspectrum (LC-MS, APCI) m/z 572 [M+H]⁺.

EXAMPLE 233

[1685]N-[2-Hydroxy-1-(hydroxymethyl)ethyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.

[1686] (Compound 233)

[1687] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and serinol (46 mg, 0.50 mmol,1.0M in DMF) were combined (reaction time 3 days at room temperature) togive 48 mg of the desired compound: Low resolution mass spectrum (LC-MS,APCI) m/z 572 [M+H]⁺.

EXAMPLE 234

[1688]N-[2-Hydroxy-1-(hydroxymethyl)ethyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.

[1689] (Compound 234)

[1690] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and serinol (46 mg, 0.50 mmol,1.0M in DMF) were combined (reaction time 3 days at room temperature) togive 46 mg of the desired compound: Low resolution mass spectrum (LC-MS,APCI) m/z 572 [M+H]⁺.

EXAMPLE 235

[1691]N-[2-Hydroxy-1-(hydroxymethyl)ethyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 235)

[1692] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and serinol (46 mg, 0.50 mmol,1.0M in DMF) were combined (reaction time 3 days at room temperature) togive 40 mg of the desired compound: Low resolution mass spectrum (LC-MS,APCI) m/z 604 [M+H]⁺.

EXAMPLE 236

[1693]N-[2-Hydroxy-1-(hydroxymethyl)ethyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.

[1694] (Compound 236)

[1695] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and serinol (46 mg, 0.50 mmol,1.0M in DMF) were combined (reaction time 3 days at room temperature) togive 45 mg of the desired compound: Low resolution mass spectrum (LC-MS,APCI) m/z 604 [M+H]⁺.

EXAMPLE 237

[1696]N-[2-Hydroxy-1-(hydroxymethyl)ethyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.

[1697] (Compound 237)

[1698] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and serinol (46mg, 0.50 mmol, 1.0M in DMF) were combined (reaction time 3 days at roomtemperature) to give 23 mg of the desired compound: Low resolution massspectrum (LC-MS, APCI) m/z 604 [M+H]⁺.

EXAMPLE 238

[1699]N-(2-Furylmethyl)-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy-}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 238)

[1700] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and furfurylamine (29 mg, 0.30mmol, 0.6M in DMF) were combined to give 56 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 578 [M+H]⁺.

EXAMPLE 239

[1701]N-(2-Furylmethyl)-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 239)

[1702] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and furfurylamine (29 mg, 0.30mmol, 0.6M in DMF) were combined to give 56 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 578 [M+H]⁺.

EXAMPLE 240

[1703]N-(2-Furylmethyl)-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 240)

[1704] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and furfurylamine (29 mg, 0.30mmol, 0.6M in DMF) were combined to give 54 mg of the desired compound:Low resolution mass spectrum (LC-MS, APCI) m/z 578 [M+H]⁺.

EXAMPLE 241

[1705]N-[(1R)-1-(Hydroxymethyl)propyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 241)

[1706] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and (R)-2-amino-1-butanol (45 mg,0.50 mmol, 1.0M in DMF) were combined to give 35 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 602 [M+H]⁺.

EXAMPLE 242

[1707]N-[(1R)-1-(Hydroxymethyl)propyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 242)

[1708] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and (R)-2-amino-1-butanol (45 mg,0.50 mmol, 1.0M in DMF) were combined to give 39 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 602 [M+H]⁺.

EXAMPLE 243

[1709]N-[(1R)-1-(Hydroxymethyl)propyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 243)

[1710] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and (R)-2-amino-1-butanol (45 mg,0.50 mmol, 1.0M in DMF) were combined to give 32 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 602 [M+H]⁺.

EXAMPLE 244

[1711]N-[(1R)-1-(Hydroxymethyl)propyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 244)

[1712] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and (R)-2-amino-1-butanol (45 mg,0.50 mmol, 1.0M in DMF) were combined to give 51 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 570 [M+H]⁺.

EXAMPLE 245

[1713]N-[(1R)-1-(Hydroxymethyl)propyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 245)

[1714] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and (R)-2-amino-1-butanol (45 mg,0.50 mmol, 1.0M in DMF) were combined to give 53 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 570 [M+H]⁺.

EXAMPLE 246

[1715]N-[(1R)-1-(Hydroxymethyl)propyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 246)

[1716] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and (R)-2-amino-1-butanol (45 mg,0.50 mmol, 1.0M in DMF) were combined to give 50 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 570 [M+H]⁺.

EXAMPLE 247

[1717]4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-[(2S)-2-methylbutyl]benzamide.(Compound 247)

[1718] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and (S)-2-methylbutylamine (26 mg,0.30 mmol, 0.6M in DMF) were combined to give 60 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 600 [M+H]⁺.

EXAMPLE 248

[1719]3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl-N-[(2S)-2-1-methylbutyl]benzamide.(Compound 248)

[1720] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and (S)-2-methylbutylamine (26 mg,0.30 mmol, 0.6M in DMF) were combined to give 58 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 600 [M+H]⁺.

EXAMPLE 249

[1721]2-[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-[(2S)-2-methylbutyl]benzamide.(Compound 249)

[1722] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and (S)-2-methylbutylamine (26 mg,0.30 mmol, 0.6M in DMF) were combined to give 60 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 600 [M+H]⁺.

EXAMPLE 250

[1723]2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-[(2S)-2-1-methylbutyl]benzamide.(Compound 250)

[1724] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and (S)-2-methylbutylamine (26 mg,0.30 mmol, 0.6M in DMF) were combined to give 57 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 568 [M+H]⁺.

EXAMPLE 251

[1725]4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-[(2S)-2-methylbutyl]benzamide.(Compound 251)

[1726] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and (S)-2-methylbutylamine (26 mg,0.30 mmol, 0.6M in DMF) were combined to give 56 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 568 [M+H]⁺.

EXAMPLE 252

[1727]3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-[(2S)-2-methylbutyl]benzamide.(Compound 252)

[1728] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and (S)-2-methylbutylamine (26 mg,0.30 mmol, 0.6M in DMF) were combined to give 57 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 568 [M+H]⁺.

EXAMPLE 253

[1729]N-(2-Hydroxypropyl)-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 253)

[1730] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and 1-amino-2-propanol (23 mg,0.30 mmol, 0.6M in DMF) were combined to give 23 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 588 [M+H]⁺.

EXAMPLE 254

[1731]N-(2-Hydroxypropyl)-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide.(Compound 254)

[1732] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and 1-amino-2-propanol (23 mg,0.30 mmol, 0.6M in DMF) were combined to give 27 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 588 [M+H]⁺.

EXAMPLE 255

[1733]N-(2-Hydroxypropyl)-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl))methyl]sulfonyl}benzamide.(Compound 255)

[1734] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and 1-amino-2-propanol (23 mg,0.30 mmol, 0.6M in DMF) were combined to give 42 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 588 [M+H]⁺.

EXAMPLE 256

[1735]N-(2-Hydroxypropyl)-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 256)

[1736] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and 1-amino-2-propanol (23 mg,0.30 mmol, 0.6M in DMF) were combined to give 46 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]⁺.

EXAMPLE 257

[1737]N-(2-Hydroxypropyl)-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 257)

[1738] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and 1-amino-2-propanol (23 mg,0.30 mmol, 0.6M in DMF) were combined to give 32 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]⁺.

EXAMPLE 258

[1739]N-(2-Hydroxypropyl)-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide.(Compound 258)

[1740] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and 1-amino-2-propanol (23 mg,0.30 mmol, 0.6M in DMF) were combined to give 46 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]⁺.

EXAMPLE 259

[1741]3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-(2-methoxyethyl)benzamide.(Compound 259)

[1742] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 2-methoxyethylamine(23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 49 mg of thedesired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 556[M+H]⁺.

EXAMPLE 260

[1743]2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-(2-methoxyethyl)benzamide.(Compound 260)

[1744] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and 2-methoxyethylamine (23 mg,0.30 mmol, 0.6M in DMF) were combined to give 43 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]⁺.

EXAMPLE 261

[1745]4-{[(2-{[1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-(2-methoxyethyl)benzamide.(Compound 261)

[1746] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicacid (50 mg, 0.10 mmol, 0.20M in DMF) and 2-methoxyethylamine (23 mg,0.30 mmol, 0.6M in DMF) were combined to give 56 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]⁺.

EXAMPLE 262

[1747]4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-(2-methylethyl)benzamide.(Compound 262)

[1748] Using the method in Example 172,4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and 2-methoxyethylamine (23 mg,0.30 mmol, 0.6M in DMF) were combined to give 38 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 588 [M+H]⁺.

EXAMPLE 263

[1749] 3-{[(2-{[(1S)-2-(1H-Inimidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-(2-methoxyethyl)benzamide.(Compound 263)

[1750] Using the method in Example 172,3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and 2-methoxyethylamine (23 mg,0.30 mmol, 0.6M in DMF) were combined to give 42 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 588 [M+H]⁺.

EXAMPLE 264

[1751]2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)-methyl]sulfonyl}-N-(2-methoxyethyl)benzamide.(Compound 264)

[1752] Using the method in Example 172,2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicacid (53 mg, 0.10 mmol, 0.20M in DMF) and 2-methoxyethylamine (23 mg,0.30 mmol, 0.6M in DMF) were combined to give 27 mg of the desiredcompound: Low resolution mass spectrum (LC-MS, APCI) m/z 588 [M+H]⁺.

EXAMPLE 265

[1753] The pharmaceutical utility of compounds of this invention areindicated by the following assay for inhibitors of protein:farnesyltransferease (PFT) or farnesyl protein transferase (FPT).

[1754] PFT Inhibitory Activity

[1755] The PFT or FPT inhibitory activity of compounds of the presentinvention were assayed in HEPES buffer (pH 7.4) containing 5 mMpotassium phosphate and 20 μM ZnCl₂. The solution also contained 5 mMDTT (dithiothreitol), 5 mM MgCl₂, and 0.1% PEG 8000. Assays wereperformed in 96 well plates (Wallec) and employed solutions composed ofvarying concentrations of a compound of the present invention in 10%DMSO (dimethylsulfoxide). Upon addition of both substrates, radiolabeledfarnesyl pyrophosphate ([¹³H], specific activity 15-30 Ci/mmol, finalconcentration 134 nM) and (biotinyl)-Ahe-Thr-Lys-Cys-Val-Ile-Met([3aS[3a alpha, 4 beta, 6aalpha]-hexahydro-2-oxo-1H-thieno[3,4-d]imidazole-5-pentanoicacid]-[7-aminoheptanoic acid]-Thr-Lys-Cys-Val-Ile-Met) (Ahe is7-aminoheptanoic acid, Thr is threonine, Lys is lysine, Cys is cysteine,Val is valine, Ile is isoleucine, and Met is methionine) (finalconcentration 0.2 μM), the enzyme reaction was started by addition ofSF9 affinity purified rat FPT. After incubation at 30° C. for 30minutes, the reaction was terminated by diluting the reaction 2.5-foldwith a stop buffer containing 1.5 M magnesium acetate, 0.2 M H₃PO₄, 0.5%BSA (bovine serum albumin), and strepavidin beads (Amersham) at aconcentration of 1.3 mg/mL. After allowing the plate to settle for 30minutes at room temperature, radioactivity was quantitated on amicroBeta counter (Model 1450, Wallec). The assay was also carried outwithout 5 mM potassium phosphate.

[1756] The compounds of the present invention have inhibitory activities(IC₅₀) ranging from 0.1 to about 40 nM in the above assay. The compoundsof Formula I, which are a sub-genus of the compounds disclosed inWO98/34921, which is PCT Application No. PCT/US98/03025, have inhibitoryactivities (IC₅₀) ranging from 0.1 to about 30 nM in the above assay.PCT/US98/03025 discloses the compound of Example 80, which is6-[2-(1H-1-Imidazolyl)-1-phenylethoxy]-1,2,3,4-tetrahydro-1-naphthalenone,and has the following structure:

[1757] The compound of Example 80 has an IC₅₀ of 73 nM. The above datasupports the conclusion that the compounds of Formula I have surprisingand unexpectedly high inhibitory activities as compared to the compoundof Example 80 in PCT/US98/03025.

[1758] The data in Table 2 below shows the FPT inhibitory activity ofspecific compounds of the present invention. TABLE 2 Example FTase IC₅₀nM  1 0.3  2 3  3 0.3  4 0.3  5 2  6 0.4  7 6  8 3  9 4  10 0.3   10a30.5   10b 2.5   10c 5.3   10d 5.5  11 0.2  12 4  13 2  14 26  15 0.2 16 0.8  17 0.3  18 8  19 14  19a 1.9   19b 3.6   19c 1.4   19d 1.9   200.4  21 8  22 26  23 11  24 0.4  25 5  26 2   26a 5   26b 0.85   26c 0.2 27 10  28 13  29 0.1  30 0.2  31 10  32 25  33 4  34 25  35 15  36 7 37 13   37a 14  38 31  39 1   39a 38  40 7.3   40a 0.65   40b 6   40c1.2   40d 9   40e 2.5   40f 13   40g 0.8  41 14  42 1.5   42a 1.1   42b3.5   42c 3.5   42d 2   42e 1.5   42f 4   42g 1.5   42h 8   42i 1.5  42j 4.4   42k 16  43 1.7  44 0.2   44a 0.87   44b 3.1  45 2  46 37  472  48 35  49 17  50 8  51 3  52 8  53 5  54 5  55 1  56 15  57 7  58 0.5  58a 1.6  59 12  60 29  61 7  62 10  63 0.2   63a 0.4   63b 0.94    63ba 0.16   63c 0.3   63d 0.17   63e 9.7   63f 13   63g 9.5   63h2.5   63i 1.8   63j 1.5   63k 2   63l 5.5   63m 1   63n 7   63o 4   63p0.55   63q 0.5   63r 35  64 11  65 0.4  66 12  67 1  68 1  69 0.7  70 7 71 4  72 5  73 2  74 3  75 3  76 1  77 1  78 0.8  79 0.8  80 1  81 4 82 9  83 18  84 4  85 10  86 5  87 7  88 7  89 7  90 5  91 5  92 4  933  94 3  95 7  96 5  97 6  98 3  99 5 100 4 101 3 102 5 103 5 104 5 1055 106 6 107 10 108 3 109 30 110 2 111 3 112 17 113 3 114 2 115 5 116 5117 1 118 4 119 12 120 13 121 4 122 16 123 30 124 5 125 15 126 19 127 3128 3 129 8 130 1 131 1 132 1 133 1 134 1 135 4 136 18 137 4 138 4 13911 140 19 141 0.35 142 0.55 143 1.4 144 35 145 16 146 34 147 19 148 5.3149 3 150 16 151 19 152 5 153 15 154 2.6 155 20 156 5 157 4 158 4 1595.5 160 10 161 5 162 8 163 5 164 5.3 165 6.4 166 30 167 7 168 10 169 7170 7 171 6 172 5 173 4 174 3 175 10 176 7 177 3 178 8 179 6 180 6 18120 182 10 183 7 184 9 185 4 186 4 187 7 188 4 189 10 190 8 191 2 192 7193 5 194 0.2 195 0.2 196 0.2 197 0.2 198 0.2 199 0.4 200 0.24 201 0.2202 0.2 203 1.2 204 0.65 205 0.2 206 0.8 207 0.2 208 0.2 209 0.2 210 0.2211 0.2 212 0.2 213 0.2 214 0.37 215 0.2 216 0.4 217 0.2 218 0.2 2190.47 220 0.2 221 0.2 222 0.2 223 0.24 224 0.2 225 0.2 226 0.2 227 0.2228 0.2 229 0.55 230 0.2 231 0.2 232 0.2 233 0.45 234 0.25 235 15 2360.2 237 0.28 238 0.2 239 0.3 240 0.2 241 0.26 242 0.2 243 0.2 244 0.2245 0.2 246 0.2 247 0.2 248 0.2 249 0.25 250 0.2 251 0.2 252 0.2 253 0.7254 1 255 0.2 256 0.2 257 0.2 258 0.2 259 0.2 260 0.2 261 0.2 262 0.8263 0.2 264 0.2

[1759] The enzyme inhibitory activity of the invention compounds, asestablished in the foregoing assay, demonstrates that the compounds areuseful in preventing and treating uncontrolled cellular proliferation,and are thus useful for preventing and treating disease statescharacterized by such proliferation.

[1760] The compounds of the present invention will be used in the formof pharmaceutical formulations, and the following examples illustratetypical dosage forms.

EXAMPLE 266

[1761] Tablet Formulation Ingredient Amount Compound No. 12  50 mgLactose  80 mg Cornstarch (for mix)  10 mg Cornstarch (for paste)  8 mgMagnesium Stearate (1%)  2 mg 150 mg

[1762] Compound No. 12 is mixed with the lactose and cornstarch (formix) and blended to uniformity to a powder. The cornstarch (for paste)is suspended in 6 mL of water and heated with stirring to form a paste.The paste is added to the mixed powder, and the mixture is granulated.The wet granules are passed through a No. 8 hard screen and dried at 50°C. The mixture is lubricated with 1% magnesium stearate and compressedinto a tablet. The tablets are administered to a patient at the rate of1 to 4 each day for prevention and treatment of atherosclerosis.

EXAMPLE 267 Parenteral Solution

[1763] In a solution of 700 mL of propylene glycol and 200 mL of waterfor injection is added 20.0 g of Compound No. 8. The mixture is stirredand the pH is adjusted to 5.5 with hydrochloric acid. The volume isadjusted to 1000 mL with water for injection. The solution issterilized, filled into 5.0 mL ampoules, each containing 2.0 mL (40 mgof Compound No. 8), and sealed under nitrogen. The solution isadministered by injection to a patient suffering from cancer and in needof treatment.

EXAMPLE 268 Patch Formulation

[1764] Compound No. 26 (10 mg) is suspended in a mixture of mineral oil,polyisobutylene, and colloidal silicon dioxide (5 mg each). This mixtureis applied evenly to a 10 cm² microporous polypropylene membrane (whichhas a backing layer of pigmented polyester film) that controls the rateof delivery of active agent to the skin surface of a patient. Themembrane is layered onto an adhesive formulation of polyisobutylene, andthe mixture is covered with a protective slit release liner of polyesterthat is removed immediately before applying the patch to the chest orforearm of a patient to treat Alzheimer's disease.

[1765] The invention and the manner and process of making and using it,are now described in such full, clear, concise, and exact terms as toenable any person skilled in the art to which it pertains, to make anduse the same. It is to be understood that the foregoing describespreferred embodiments of the present invention and that modificationsmay be made therein without departing from the spirit or scope of thepresent invention as set forth in the claims. To particularly point outand distinctly claim the subject matter regarded as invention, thefollowing claims conclude this specification.

What is claimed is:
 1. A compound of formula

wherein: W is CH₂ or CH₂CH₂; R³ is hydrogen, C₁-C₆ alkyl, phenyl, orsubstituted phenyl; R^(3a) is hydrogen or C₁-C₆ alkyl; provided that R³and R^(3a) cannot both be hydrogen; further provided that when R³ isphenyl or substituted phenyl that R^(3a) is hydrogen; X is halogen,amino, C₁-C₆ alkyl, C₂-C₆ alkenyl, aryl, substituted aryl, heteroaryl,arylalkyl, substituted arylalkyl, heteroarylalkyl, substitutedheteroarylalkyl, —CH₂OR⁶, —CH₂NR⁶R^(6a), —CH₂SR⁶, or —CH₂CH₂CO₂R⁶; R⁶ ishydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, phenyl, benzyl, C₃-C₆ cycloalkyl,or substituted phenyl; R^(6a) is hydrogen or C₁-C₆ alkyl; Y is O or S;R⁵ is hydrogen, C₁-C₆ alkyl, or amino; and pharmaceutically acceptablesalts, esters, amides, and prodrugs thereof, provided that the compoundis not5-[(Diisobutylamino)-methyl]-6-(imidazol-1-yl-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one;5-Amino-6-((S)-imidazol-1-ylmethyl-2-methyl-propoxy)-3,4-dihydro-2H-napthalen-1-one;5-(3,4-Dichloro-phenylsulfanylmethyl)-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one;Cyclopentylsulfanylmethyl-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one;6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-(isopropylamino-methyl)-3,4-dihydro-2H-napthalen-1-one;5-Biphenyl-3-yl-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one;6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-phenyl-3,4-dihydro-2H-napthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-prop-2-enyl-2,3,4-trihydronaphthalen-1-one;or5-Bromo-6-(2-imidazol-1-yl-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one.2. A compound of formula

wherein: y is 0, 1, 2, or 3; R⁷ is C₁-C₆ alkyl, C₂-C₆ alkenyl, alkoxy,—O—(C₃-C₆)cycloalkyl, —O—(C₂-C₆)alkenyl, halogen, —NH₂, —CO₂H,—CO₂-alkyl, —O-phenyl, —O-substituted phenyl, —O-benzyl,—S—(C₁-C₆)alkyl, —S—(C₃-C₆)cycloalkyl, —S-phenyl, —S-substituted phenyl,—NH-phenyl, —NH-substituted phenyl, aryl, substituted aryl, heteroaryl,or substituted heteroaryl; provided that when R⁷ is —NH₂ that y is 0;further provided that when R⁷ is phenyl that y cannot be 0; andpharmaceutically acceptable salts, esters, amides, and prodrugs thereof,provided that the compound is not5-Bromo-6-(2-imidazol-1-yl-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one;5-(3,4-Dichloro-phenylsulfanylmethyl)-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-oneCyclopentylsulfanylmethyl-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one5-Biphenyl-3-yl-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one;or6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-prop-2-enyl-2,3,4-trihydronaphthalen-1-one.3. A compound of claim 1 which is selected from the group consisting of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(phenylthiomethyl)-2,3,4-trihydronaphthalen-1-;Methyl2-{[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]methylthio}benzoate;2-{[2-((1S)-2-Imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]methylthio}benzoicacid;6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-isopropylsulfanylmethyl-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(phenylamino)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(methyl-phenylamino)methyl]-2,3,4-trihydronaphthalen-1-one; Methyl4-({[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo(6,7,8-trihydronaphthyl)]methyl}methylamino)benzoate;4-({[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo(6,7,8-trihydronaphthyl)]methyl}methylamino)benzoicacid, 2,2,2-trifluoroacetic acid;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(methylethoxy)methyl]-2,3,4-trihydronaphthalen-1-onehydrochloride;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(phenylmethoxy)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(cyclopentyloxymethyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-imidazolyl-1-phenylethoxy)-5-(prop-2-enyloxymethyl)-2,3,4-trihydronaphthalen-1-one;6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-isobutoxymethyl-3,4-dihydro-2H-naphthalen-1-one;6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-propoxymethyl-3,4-dihydro-2H-naphthalen-1-one;5-(1-Ethyl-propoxymethyl)-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one;(±)-5-sec-Butoxymethyl-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-phenylethyl)-2,3,4-trihydronaphthalen-1-one;5-(2H-Benzo[d]1,3-dioxolan-5-yl)-6-((1S)-2-imidazolyl-1-phenylethoxy)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(3-chlorophenyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-naphthyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-(2-pyridyl)ethyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-(4-pyridyl)ethyl)-2,3,4-trihydronaphthalen-1-one;(S)-6-(-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(2-pyridin-3-yl-ethyl)-3,4-dihydro-2H-naphthalen-1-one;(S)-6-(-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(2-pyridin-3-yl-ethyl)-3,4-dihydro-2H-naphthalen-1-one;Methyl4-{2-[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]ethyl}benzoate;Methyl4-{2-[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]ethyl}benzoate;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[2-(4-fluorophenyl)ethyl]-2,3,4-trihydronaphthalen-1-one;Methyl3-[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]propanoate;3-[2-((1S)-2-Imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]propanoicacid;4-{[2-((1S)-2-Imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]methyl}benzenecarbonitrile;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-bromo-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(3-thienyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(3-furyl)-2,3,4-trihydronaphthalen-1-one,2,2,2-trifluoroacetic acid;5-Amino-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-phenylpropyl)-2,3,4-trihydronaphthalen-1-one;6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(2-thiophen-3-yl-ethyl)-3,4-dihydro-2H-naphthalen-1-one;6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(3-phenyl-propyl)-3,4-dihydro-2H-naphthalen-1-one;6-((1S)-2-imidazolyl-1-phenylethoxy)-5-benzyl-2,3,4-trihydronaphthalen-1-one;(6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-propyl-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-methylprop-2-enyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-methylpropyl)-2,3,4-trihydronaphthalen-1-one;5-((1S)-2-Imidazolyl-1-phenylethoxy)-4-prop-2-enylindan-1-one;6-[2-(1H-Imidazol-1-yl)-1,1-dimethylethoxy]-5-(2-phenylethyl)-3,4-dihydro-1(2H)-naphthalenone;6-((1S)-2-imidazolyl-1-phenylethylthio)-5-propyl-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethylthio)-5-(2-phenylethyl)-2,3,4-trihydronaphthalen-1-one;(S)-6-(1-imidazol-1-ylmethyl-2-methyl-propoxy)-5-(2-pyridin-4-yl-ethyl)-3,4-dihydro-2H-naphthalen-1-one;(S)-6-[-1-(4-Fluoro-phenyl)-2-imidazol-1-yl-1-ethoxy]-5-(2-pyridin-4-yl-ethyl)-3,4-dihydro-2H-naphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(methoxymethyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(methoxymethyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(phenoxymethyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[3-(tert-butyl)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[2-(methylethyl)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(3-chlorophenoxy)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[2-methyl-5-(methylethyl)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(3,5-dimethoxyphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[4-(methylethyl)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-5,6,7,8-tetrahydro-naphthyloxymethyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[3-(methylethyl)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[2-(methylethoxy)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-ethoxyphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-ethoxyphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(3-ethylphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one;Methyl2-{[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]methoxy}benzoate;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-ethylphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-naphenyloxymethyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-chloro-5-methylphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[2-(methylpropyl)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one; Methyl3-{[2-((1S)-2-imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]methoxy}benzoate;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2,4,6-trimethylphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[4-(methylpropyl)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[4-(trifluoromethyl)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2H-benzo[d]1,3-dioxolan-5-yloxymethyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2H-benzo[d]1,3-dioxolan-5-yloxymethyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(8-quinolyloxymethyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-chlorophenoxy)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(3-methylphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-methylphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-fluorophenoxy)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(3-fluorophenoxy)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-fluorophenoxy)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(naphenyloxymethyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(3-methoxyphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-chlorophenoxy)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(6-quinolyloxymethyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-bromophenylthio)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-fluorophenylthio)methyl]-2,3,4-trihydronaphthalen-1-one;N-(4-{[2-((1S)-2-Imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]methylthio}phenyl)acetamide;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-hydroxyphenylthio)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-methylphenylthio)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-methylpropylthio)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(cyclohexylthiomethyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-bromophenylthio)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-chlorophenylthio)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2,6-dichlorophenylthio)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-methoxyphenylthio)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-methylphenylthio)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-methoxyphenylthio)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-nitrophenylthio)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(3-methoxyphenylthio)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-chlorophenylthio)methyl]-2,3,4-trihydronaphthalen-1-one;2-{[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-napthalen-1-ylmethyl]-amino}-benzonitrile;5-[(4-Bromo-phenylamino)-methyl]-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one;5-[(4-Fluoro-phenylamino)-methyl]-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one;5-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylamino)-methyl]-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-napthalen-1-one;Methyl4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoate;Methyl3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoate;4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicAcid; and3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoicAcid.
 4. A compound of formula

wherein: R⁹ is phenyl, substituted phenyl, heteroaryl, or C₁-C₆ alkyl;R¹⁰ is hydrogen, C₁-C₆ alkyl, or C₁-C₆ substituted alkyl; y is 0, 1, 2,or 3; R¹¹ is —O-substituted alkyl, —O-aryl, —O-substituted aryl,—O-aryl-heteroaryl, —O-heteroaryl, —O-substituted heteroaryl,—O-phenyl-O—CF₃, —O-phenyl-O-phenyl, —S-aryl, —S-substituted aryl,—S-arylalkyl, —S(O)z-substituted alkyl, —S(O)z-substituted arylalkyl,—S(O)z-heteroaryl, —S(O)z-heteroarylalkyl, —S(O)z-substitutedheteroaryl, —SO-alkyl, —SO₂-alkyl, —SO-aryl, —SO₂-aryl, —SO-substitutedaryl, —SO₂-substituted aryl, —SO-arylalkyl, —SO₂-arylalkyl,—S(O)z-phenyl-CONH—R¹³, —NHSO₂—R¹⁴, —NHCO—R¹⁴, NHCO-heteroaryl-O-aryl,NHCO-heteroaryl-substituted aryl, NHCOC(substituted alkyl)N—HCO₂-alkyl,—NHCO—C(substituted alkyl)amino, —NHCO₂-alkyl, —NH-aryl, —NH-substitutedaryl, —NH-heteroaryl, —NH—(CH₂)₂—O-heteroaryl, —N(CO-alkyl)substitutedaryl, -aryl-CO-alkyl,

z is 0, 1 or 2; R¹³ is alkyl, substituted alkyl, alkenyl, alkynyl,cycloalkyl, or heteroarylalkyl; R¹⁴ is aryl, substituted aryl,arylalkyl, heteroaryl, heteroarylalkyl, or substituted heteroaryl;provided that when R¹¹ is —O-aryl, —O-substituted aryl, —S-aryl,—S-arylalkyl, —S-substituted aryl, —NH-aryl, or —NH-substituted arylthat the aryl is not phenyl; and pharmaceutically acceptable salts,esters, amides, and prodrugs thereof.
 5. A compound of claim 4 whereinR⁹ is phenyl or heteroaryl.
 6. A compound of claim 4 wherein R⁹ isphenyl.
 7. A compound of claim 4 wherein R⁹ is heteroaryl.
 8. A compoundof claim 4 wherein R¹⁰ is hydrogen.
 9. A compound of claim 4 wherein yis O.
 10. A compound of claim 4 wherein y is
 1. 11. A compound of claim4 wherein R¹¹ is —S(O)z-substituted alkyl, —S(O)z-substituted arylalkyl,—S(O)z-heteroaryl, —S(O)z-heteroarylalkyl, —S(O)z-substitutedheteroaryl, —SO₂-alkyl, —SO₂-aryl, —SO₂-substituted aryl, —SO₂ —arylalkyl, —S(O)z-phenyl-CONH—R¹³, —NHSO₂—R¹⁴, or —NHCO—R¹⁴.
 12. Acompound of claim 4 wherein R¹ is —NHCO—R¹⁴.
 13. A compound of claim 12wherein R¹⁴ is heteroaryl.
 14. A compound of claim 4 which is selectedfrom the group consisting of6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(phenylsulfinyl)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(phenylsulfonyl)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[(methylethyl)sulfonyl]methyl}-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(4-pyridylthiomethyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-pyridylthiomethyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-pyridylsulfonyl)methyl]-2,3,4-trihydronaphthalen-1-one hydrochloride;6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(naphthalen-1-ylsulfanylmethyl)-3,4-dihydro-2H-naphthalen-1-one;[2-(2-Imidazol-1-yl-1(S)-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethylsulfanyl]-aceticacid methyl ester;5-(3,4-Dichloro-benzylsulfanylmethyl)-6-((1S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one;(S)-6-{2-[2-(Hydroxymethyl)-1H-imidazol-1-yl]-1-phenylethoxy}-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-methoxyethoxy)-methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[2-(1-oxy(2-pyridyl))ethyl]-2,3,4-trihydronaphthalen-1-one;(S)-6-(2-Imidazol-1-yl-1-phenyl-ethoxy)-5-[2-(1-oxy-pyridin-4-yl)-ethyl]-3,4-dihydro-2H-naphthalen-1-one;(4-{2-[2-((1S)-2-Imidazolyl-1-phenylethoxy)-5-oxo(6,7,8-trihydronaphthyl)]ethyl}phenyl)-N-methylcarboxamide;N-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-benzenesulfonamide;N-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-1-phenyl-methanesulfonamide;N-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-2-pyridin-2-yl-acetamide;Pyridine-2-carboxylic acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide;Isoquinoline-1-carboxylic acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide;Isoquinoline-3-carboxylic acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide;Pyrazine-2-carboxylic acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide;5-(4-Chloro-phenyl)-oxazole-4-carboxylic acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide;N-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-2-chloro-nicotinamide;N-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-2-phenoxy-nicotinamide;Quinoline-8-carboxylic acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide;[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-carbamicacid tert-butyl ester;N-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-benzenesulfonamide;N-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-4-methoxy-benzenesulfonamide;2,4-Difluoro-N-[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-benzenesulfonamide;compound with trifluoro-acetic acid;2-{[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-sulfamoyl}-benzoicacid methyl ester; compound with trifluoro-acetic acid;2,5-Dichloro-thiophene-3-sulfonic acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-amide;compound with trifluoro-acetic acid;3-Chloro-N-[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-benzenesulfonamide;compound with trifluoro-acetic acid; Naphthalen-2-sulfonic acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-amide;compound with trifluoro-acetic acid;N-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-C-phenyl-methanesulfonamide;Pyridine-2-carboxylic acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-amide;N-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-benzamide;((S)-1-{[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-carbamoyl}-3-methylsulfanyl-propyl)-carbamicacid tert-butyl ester;(S)-2-Amino-N-[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-4-methylsulfanyl-butyramide;2-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-isoindole-1,3-dione;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-phenoxy-2,3,4-trihydronaphthalen-1-one;6-((S)-1-Imidazol-1-ylmethyl-2-methyl-propoxy)-5-(propane-2-sulfonylmethyl)-3,4-dihydro-2H-napthalen-1-one;Isoquinoline-1-carboxylic acid[2-((S)-1-imidazol-1-ylmethyl-2-methyl-propoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide;(S)-6-[-1-(2,4-Difluoro-phenyl)-2-imidazol-1-yl-1-ethoxy]-5-(pyridin-2-ylsulfonylmethyl)-3,4-dihydro-2H-naphthalen-1-one;6-{[1-(1H-Imidazol-1-ylmethyl)pentyl]oxy}-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-pyrrolylphenoxy)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(indol-4-yloxymethyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(6-methyl(3-pyridyloxy))methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(6-methyl(3-pyridyloxy))methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(8-quinolyloxymethyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[4-(trifluoromethoxy)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-{[4-(phenoxy)phenoxy]methyl}-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(6-quinolyloxymethyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-hydroxyethylthio)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2-phenylethylthio)methyl]-2,3,4-trihydronaphthalen-1-one; Methyl3-{[2-((1S)-2-Imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]methylthio}propanoate;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(imidazol-2-ylthiomethyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(1H-1,2,4-triazol-3-ylthiomethyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(1-methylimidazol-2-ylthio)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(benzothiazol-2-ylthiomethyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(5-chlorobenzothiazol-2-ylthio)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-furylthiomethyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(5-nitrobenzimidazol-2-ylthio)methyl]-2,3,4-trihydronaphthalen-1-one;2-{[2-((1S)-2-Imidazolyl-1-phenylethoxy)-5-oxo-6,7,8-trihydronaphthyl]methylthio}pyridine-3-carboxylicacid;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(methyl(1,2,3,4-tetraazol-5-ylthio))methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(2,2,2-trifluoroethylthio)methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-naphenylthiomethyl)-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-[(4-methyl(1,2,4-triazol-3-ylthio))methyl]-2,3,4-trihydronaphthalen-1-one;6-((1S)-2-Imidazolyl-1-phenylethoxy)-5-(2-quinolylthiomethyl)-2,3,4-trihydronaphthalen-1-one;6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(4-methoxy-benzenesulfinylmethyl)-3,4-dihydro-2H-napthalen-1-one;6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(pyridine-2-sulfinylmethyl)-3,4-dihydro-2H-napthalen-1-one;6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-(propane-2-sulfinylmethyl)-3,4-dihydro-2H-napthalen-1-one;N-[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-N-β-tolyl-acetamide;6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-[1H-indazol-5-ylamino)methyl]-3,4-dihydro-2H-napthalen-1-one;6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(4-phenyl-piperazin-1-ylmethyl)-3,4-dihydro-2H-napthalen-1-one;6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(4-pyridin-2-yl-piperazin-1-ylmethyl)-3,4-dihydro-2H-napthalen-1-one;6-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-(quinolin-8-ylaminomethyl)-3,4-dihydro-2H-napthalen-1-one;5-(3,4-Dichloro-benzylsulfanylmethyl)-6-((1S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one;Methyl2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoate;Methyl4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoate;Methyl4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl-3-oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoate;2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicAcid;4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicAcid;3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoicAcid;2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl)-N-methylbenzamide;N-(2-Hydroxyethyl)-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoyl-β-alanine;N-2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoyl-β-alanine;N-3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoyl-β-alanine;N-2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoyl-o-alanine;N-4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoyl-β-alanine;N-3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoyl-1-alanine;N-(2-Hydroxyethyl)-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-(2-Hydroxyethyl)-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-(2-Hydroxyethyl)-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-(2-Hydroxyethyl)-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-(2-Hydroxyethyl)-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-[2-(Dimethylamino)ethyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-[2-(Dimethylamino)ethyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]-sulfanyl}benzamide;N-[2-(Dimethylamino)ethyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-[2-(Dimethylamino)ethyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-[2-(Dimethylamino)ethyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-[2-(Dimethylamino)ethyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;Ethyl3-[(2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoyl)amino]propanoate;Ethyl4-[(2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1naphthalenyl)methyl]sulfonyl}benzoyl)amino]propanoate; Ethyl2-[(2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoyl)amino]propanoate;Ethyl2-[(2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoyl)amino]propanoate;Ethyl3-[(2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoyl)amino]propanoate; Ethyl4-[(2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoyl)amino]propanoate;4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-methylbenzamide;3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-methylbenzamide;4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-methylbenzamide;3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-methylbenzamide;2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-methylbenzamide;N-[(2R)-2-Hydroxypropyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-[(2R)-2-Hydroxypropyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-[(2S)-2-Hydroxypropyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-[(2S)-2-Hydroxypropyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-[(2S)-2-Hydroxypropyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-[(2S)-2-Hydroxypropyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-[(2S)-2-Hydroxypropyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-[(2S)-2-Hydroxypropyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-[(2R)-2-Hydroxypropyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-[(2R)-2-Hydroxypropyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-[(2R)-2-Hydroxypropyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-Allyl-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-Allyl-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-Allyl-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-Allyl-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-Allyl-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-Allyl-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-(2-propynyl)benzamide;4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-(2-propynyl)benzamide;3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-(2-propynyl)benzamide;4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-(2-propynyl)benzamide;3-{[(2-1-[(S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-(2-propynyl)benzamide;2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-(2-propynyl)benzamide;N-Cyclopentyl-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-Cyclopentyl-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-Cyclopentyl-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-Cyclopentyl-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-Cyclopentyl-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-Cyclopentyl-2-{((2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-Cyclopropyl-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-Cyclopropyl-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-Cyclopropyl-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-Cyclopropyl-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-Cyclopropyl-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-Cyclopropyl-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-(2-Furylmethyl)-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-(2-Furylmethyl)-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-(2-Furylmethyl)-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-[2-Hydroxy-1-(hydroxymethyl)ethyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-[2-Hydroxy-1-(hydroxymethyl)ethyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-[2-Hydroxy-1-(hydroxymethyl)ethyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-[2-Hydroxy-1-(hydroxymethyl)ethyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-[2-Hydroxy-1-(hydroxymethyl)ethyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-[2-Hydroxy-1-(hydroxymethyl)ethyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-(2-Furylmethyl)-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-(2-Furylmethyl)-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-(2-Furylmethyl)-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-[(1R)-1-(Hydroxymethyl)propyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-[(1R)-1-(Hydroxymethyl)propyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-[(1R)-1-(Hydroxymethyl)propyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-[(1R)-1-(Hydroxymethyl)propyl]-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-[(1R)-1-(Hydroxymethyl)propyl]-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-[(1R)-1-(Hydroxymethyl)propyl]-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-[(2S)-2-methylbutyl]benzamide;3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-[(2S)-2-methylbutyl]benzamide;2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-[(2S)-2-methylbutyl]benzamide;2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-[(2S)-2-methylbutyl]benzamide;4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-[(2S)-2-methylbutyl]benzamide;3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-[(2S)-2-methylbutyl]benzamide;N-(2-Hydroxypropyl)-4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-(2-Hydroxypropyl)-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-(2-Hydroxypropyl)-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzamide;N-(2-Hydroxypropyl)—{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;N-(2-Hydroxypropyl)-2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;-351N-(2-Hydroxypropyl)-3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzamide;3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-(2-methoxyethyl)benzamide;2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-(2-methoxyethyl)benzamide;4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}-N-(2-methoxyethyl)benzamide;4-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-(2-methoxyethyl)benzamide;3-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-(2-methoxyethyl)benzamide;and2-{[(2-{[(1S)-2-(1H-Imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}-N-(2-methoxyethyl)benzamide.15. A compound which is Pyridine-2-carboxylic acid[2-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide;16. A compound of the formula

wherein: y is 0, 1, 2, or 3; R¹⁵ is lower alkyl, lower alkenyl, alkoxy,substituted alkoxy, arylalkoxy, —O-cycloalkyl, —O-alkenyl, alkylthio,hydroxy, thiol, cyano, halogen, —CF₃, —NO₂, —NH₂, —NH-alkyl,—NH-dialkyl, —NHCO-alkyl, —CO₂H, —CO₂-alkyl, —SO₃H, —O-aryl,—O-substituted aryl, —O-heteroaryl, —O-substituted heteroaryl, —S-alkyl,—S-substituted alkyl, —S-cycloalkyl, —S-aryl, —S-substituted aryl,—S-heteroaryl, —S-substituted heteroaryl, —SO₂NH₂, —SO₂NH-alkyl,—SO-aryl, —SO₂-aryl, —SO₂-substituted aryl, —SO₂-alkyl, —SO₂-heteroaryl,—SO₂-substituted heteroaryl, —NHSO₂-aryl, —NHCO-aryl, —NHCO-heteroaryl,—NHCO₂-alkyl, —NH— aryl, —NH-substituted aryl, aryl, substituted aryl,heteroaryl, and substituted heteroaryl; Y² is NR¹⁶, O, S, orCR¹⁷R^(17a); R¹⁶ is hydrogen, lower alkyl, aryl, arylalkyl, heteroaryl,or cycloalkyl; R¹⁷ and R^(17a) are each independently hydrogen, loweralkyl, lower alkenyl, cycloalkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl,substituted heterocycloalkyl, heterocyclalkylalkyl, substitutedheterocycloalkylalkyl, halogen, trifluoromethyl, —OR¹⁹, NR¹⁹R^(19a),NHSO₂R¹⁹, —S(O)_(z)R¹⁹, —SO₂NHR¹⁹, —OCOR¹⁹, —CH₂OR¹⁹, —CH₂NR¹⁹R^(19a),—CH₂S(O)_(z)R¹⁹, —CH₂NHSO₂R¹⁹, —CH₂S(O)_(z)R¹⁹, —CH₂SO₂NHR¹⁹, or—CH₂OCOR¹⁹; R¹⁹ and R^(19a) are each independently hydrogen, loweralkyl, aryl, arylalkyl, heteroaryl, or cycloalkyl; provided that one ofA, B, and C is N while the other two are CH; and pharmaceuticallyacceptable salts, esters, amides, and prodrugs thereof.
 17. A compoundof claim 16 wherein A is N while B and C are CH.
 18. A compound of claim16 wherein B is N while A and C are CH.
 19. A compound of claim 16wherein Y² is O.
 20. A compound of claim 16 wherein y is 2 and R¹⁵ isaryl or heteroaryl.
 21. A compound of claim 16 wherein y is O.
 22. Acompound of claim 16 wherein y is
 1. 23. A compound of claim 16 whereinR¹⁵ is —O-substituted aryl, —O-heteroaryl, —O-substituted heteroaryl,—S-alkyl, —S-substituted alkyl, —S-cycloalkyl, —S-aryl, —S-substitutedaryl, —S-heteroaryl, —S-substituted heteroaryl, —SO₂NH₂, —SO₂NH-alkyl,—SO-aryl, —SO₂-aryl, —SO₂-substituted aryl, —SO₂-alkyl, —SO₂-heteroaryl,—SO₂-substituted heteroaryl, —NHSO₂-aryl, —NHCO-aryl, —NHCO-heteroaryl,—NHCO₂-alkyl, —NH-aryl, —NH-substituted aryl, aryl, substituted aryl,heteroaryl, or substituted heteroaryl.
 24. A compound of claim 16wherein R¹⁵ is aryl, heteroaryl, —SO₂-alkyl, —SO₂-heteroaryl, or—NHCO-heteroaryl.
 25. A compound of claim 16 wherein R¹⁵ is —SO₂-alkyl,—SO₂-heteroaryl, or —NHCO-heteroaryl.
 26. A compound of claim 16 whichis selected from the group consisting of(±)-6-(2-Imidazolyl-1-(2-pyridyl)ethoxy)-5-(2-phenylethyl)-2,3,4-trihydronaphthalen-1-one;(±)-6-(2-Imidazolyl-1-(3-pyridyl)ethoxy)-5-(2-phenylethyl)-2,3,4-trihydronaphthalen-1-one;6-((S)-2-Imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-phenethyl-3,4-dihydro-2H-naphthalen-1-one;6-((S)-2-Imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-(propane-2-sulfonylmethyl)-3,4-dihydro-2H-napthalen-1-one;6-((S)-2-Imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-(pyridin-2-ylsulfonylmethyl)-3,4-dihydro-2H-napthalen-1-one;6-((S)-2-Imidazol-1-yl-1-pyridin-3-ethoxy)-5-(2-pyridin-2-yl-ethyl)-3,4-dihydro-2H-naphthalen-1-one;Isoquinoline-1-carboxylic acid[2-((S)-2-imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide;Pyrazine-2-carboxylic acid[2-((S)-2-imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide;and Cinnoline-4-carboxylic acid[2-((S)-2-imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide.27. A compound of claim 16 which is selected from the group consistingof6-((S)-2-Imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-(propane-2-sulfonylmethyl)-3,4-dihydro-2H-napthalen-1-one;6-((S)-2-Imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-(pyridin-2-ylsulfonylmethyl)-3,4-dihydro-2H-napthalen-1-one;Isoquinoline-1-carboxylic acid[2-((S)-2-imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide;and Pyrazine-2-carboxylic acid[2-((S)-2-imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl]-amide.28. A compound which is selected from the group consisting of6-((1S)-2-Imidazolyl-1-phenylethoxy)-4-(3-chlorophenyl)-2,3,4-trihydronaphthalen-1-one;(±)-6-(2-Imidazolyl-1-phenylethoxy)-4-phenyl-2,3,4-trihydro-naphthalen-1-one;(±)-6-[1-(2-Chlorophenyl)-2-imidazolylethoxy]-5-prop-2-enyl-2,3,4-trihydronaphthalen-1-one;(±)-6-[1-(2,6-Dichlorophenyl)-2-imidazolylethoxy]-5-prop-2-enyl-2,3,4-trihydronaphthalen-1-one,trifluoroacetic acid;(±)-6-(2-imidazolyl-1-(2-thienyl)ethoxy)-5-prop-2-enyl-2,3,4-trihydronaphthalen-1-one;6-[1-(1H-Imidazol-1-ylmethyl)-2-methylpropoxy]-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1-(2H)-naphthalenone;6-[1-(1H-Imidazol-1-ylmethyl)propoxy]-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone;(±)-6-[2-(2-Methyl-imidazol-1-yl)-1-phenyl-ethoxyy]-5-phenethyl-3,4-dihydro-2H-naphthalen-1-one;6-(2-Imidazol-1-yl-1-thiophen-2-yl-ethoxy)-5-(pyridine-2-sulfonylmethyl)-3,4-dihydro-2H-naphthalen-1-one;6-(2-Imidazol-1-yl-1-thiazol-2-yl-ethoxy)-5-(pyridine-2-sulfonylmethyl)-3,4-dihydro-2H-naphthalen-1-one;and6-[2-(2-Amino-imidazol-1-yl)-1-phenyl-ethoxy]-5-phenethyl-3,4-dihydro-2H-naphthalen-1-one.29. A pharmaceutically acceptable composition that comprises a compoundof claims 1, 2, 4 or 16 and a pharmaceutically acceptable carrier.
 30. Amethod of treating or preventing restenosis or atherosclerosis, themethod comprising administering to a patient having restenosis oratherosclerosis or at risk of having restenosis or atherosclerosis atherapeutically effective amount of a compound of claims 1, 2, 4 or 16.31. A method of treating cancer, the method comprising administering toa patient having cancer a therapeutically effective amount of a compoundof claims 1, 2, 4 or
 16. 32. A method of treating neurofibromin benignproliferative disorder, the method comprising administering to a patienthaving neurofibromin benign proliferative disorder a therapeuticallyeffective amount of a compound of claims 1, 2, 4 or
 16. 33. A method oftreating blindness related to retinal vascularization, the methodcomprising administering to a patient having blindness related toretinal vascularization a therapeutically effective amount of a compoundof claims 1, 2, 4 or
 16. 34. A method of treating hepatitis delta andrelated viruses, the method comprising administering to a patient havinghepatitis delta and related viruses a therapeutically effective amountof a compound of claims 1, 2, 4 or
 16. 35. A method of treatingpsoriasis, the method comprising administering to a patient havingpsoriasis a therapeutically effective amount of a compound of claims 1,2, 4 or
 16. 36. A method of treating benign prostatic hypertrophy, themethod comprising administering to a patient having benign prostatichypertrophy a therapeutically effective amount of a compound of claims1, 2, 4 or
 16. 37. A method of treating polycystic kidney disease, themethod comprising administering to a patient having polycystic kidneydisease a therapeutically effective amount of a compound of claims 1, 2,4 or 16.